Back to resultsStudy to Evaluate Safety, Pharmacokinetics and Therapeutic Activity of RO6874281 as a Combination Therapy in Participants With Unresectable Advanced and/or Metastatic Renal Cell Carcinoma (RCC)
Primary Purpose
Renal Cell Carcinoma
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Atezolizumab
Bevacizumab
RO6874281
Sponsored by
About this trial
This is an interventional treatment trial for Renal Cell Carcinoma focused on measuring Renal Cell Carcinoma, RO6874281, Atezolizumab, Bevacizumab
Eligibility Criteria
Inclusion criteria:
- Unresectable advanced and/or metastatic RCC with component of clear cell histology and/or component of sarcomatoid histology that has not been previously treated with any systemic therapy, including treatment in the adjuvant setting
- During dose escalation only, an additional population with unresectable advanced and/or metastatic 2nd line RCC patients is allowed
- At least one tumor lesion with location accessible to biopsy per clinical judgment of the treating physician
- Consent to provide an archival tumor tissue sample (if available) and to undergo baseline and on treatment tumor biopsies for pharmacodynamic biomarker analysis
- Measurable disease, as defined by RECIST v1.1. At least one lesion accessible for biopsy
- Participants with unilateral pleural effusion are eligible if they fulfill both of the following: (a) New York Heart Association (NYHA) Class 1; (b) Global initiative for obstructive lung disease (GOLD) test level 1 (forced expiratory volume in 1 second [FEV1]/ forced vital capacity [FVC] less than [<] 0.7 and FEV1 greater than or equal to [>=] 80 percent [%] predicted after inhaled bronchodilator)
Adequate hematological function: neutrophil count of ≥1.5 ≥109 cells/L, platelet count of ≥100,000/≥L, Hb ≥9 g/dL (5.6 mmol/L), lymphocytes ≥0.8 ≥109 cells/L.
Exclusion Criteria:
- Symptomatic or untreated central nervous system (CNS) metastases
- Participants with asymptomatic CNS metastases with previous or concomitant brain deficiencies, as defined in the protocol
- Participants with confirmed bilateral pleural effusion
- Episode of significant cardiovascular/cerebrovascular acute disease within 6 months prior to Cycle 1 Day 1
- Active or uncontrolled infections
- Human immunodeficiency virus (HIV) or active Hepatitis A, B, C, D and E virus (HAV, HBV, HCV, HDV and HEV) infection.
- Major surgery or significant traumatic injury <28 days prior to Cycle 1 Day 1 (excluding fine needle biopsies) or anticipation of the need for major surgery during study treatment
- Serious, non-healing wound; active ulcer; or untreated bone fracture
- Proteinuria as demonstrated by a urine protein to creatinine ratio (UPCR) of >=1.0 at screening
- History of, active or suspicion of autoimmune disease
- Concurrent use of high dose of systemic steroids. The use of inhaled, topical and ophthalmic steroids is allowed.
Sites / Locations
- Yale Cancer Center; Medical Oncology
- Northwestern Center for Clinical Research; Cancer Center
- University of Maryland Greenebaum Comprehensive Cancer Center
- Princess Margaret Cancer Center
- Herlev Hospital; Afdeling for Kræftbehandling
- Centre Léon Bérard - Centre régional de lutte contre le cancer Rhône-Alpes
- Institut Claudius Regaud; Departement Oncologie Medicale
- Universitätsklinikum Tübingen; Klinik für Urologie
- Uniklinikum, Comprehensive Cancer Center Mainfranken; Interdisziplinäres Studienzentrum mit ECTU
- Universita di Modena e Reggio Emilia;Dipartimento di Oncologia ed Ematologia
- Fondazione IRCCS Policlinico San Matteo, Oncologia
- Asan Medical Center
- Samsung Medical Center
- Clinica Universitaria de Navarra; Servicio de Oncologia
- Hospital del Mar; Servicio de Oncologia
- Hospital Univ Vall d'Hebron; Servicio de Oncologia
- Hospital Clínic i Provincial; Servicio de Oncología
- Hospital Ramon y Cajal; Servicio de Oncologia
- START Madrid-FJD, Hospital Fundacion Jimenez Diaz
- Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
- Barts & London School of Med; Medical Oncology
- The Christie
- Southampton General Hospital; Medical Oncology
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Escalation Part (Arm A): Atezolizumab, RO6874281
Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Extension Part (Arm A): Atezolizumab, RO6874281
Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Extension Part (Arm C): Atezolizumab, RO6874281
Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281
Arm Description
Participants will receive RO6874281 in combination with atezolizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has complete response (CR), treatment may be discontinued and reintroduced if progressive disease (PD), for a maximum duration of 24 months.
Participants will receive RO6874281 in combination with atezolizumab and bevacizumab until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months. Note: no new participants are being enrolled in the arm at this time.
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months. Note: no new participants are being enrolled in the arm at this time.
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab once every 3 weeks until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months. Note: no new participants are being enrolled in the arm at this time.
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once every 3 weeks until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months. Note: Arm D is closed for future enrollment
Outcomes
Primary Outcome Measures
Percentage of Participants with Dose-Limiting Toxicities (DLTs)
The first patient in each cohort and regimen will be observed for safety for one week after the administration of RO6874281and atezolizumab +-bevacizumab, prior to enrollment of additional patients in a cohort.
The DLT will be counted for each dose separately and each patient will contribute one single representative data point.
Maximum Tolerated Dose (MTD) of RO6874281
The MTD is defined as the highest dose with less than 33% probability of dose limiting toxicity (DLT).
Recommended Dose of RO6874281
The recommended dose is defined as the lowest safe dose with the best likelihood for clinical benefit.
Percentage of Participants with Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Objective response rate (ORR) defined as the number of patients who achieved an objective response (partial response (PR) plus complete response (CR)) confirmed 28 or more days later, as determined by the Investigator using RECIST v1.1 and modified RECIST criteria at any time during the study divided by the number of response-evaluable patients.
Secondary Outcome Measures
Serum RO6874281 Concentration
Pre-infusion, 1 hour (hr) post start of infusion, end of infusion (EOI), 2, 6 hr post EOI on Cycle 1 Day 1; Cycle 1 Days 2, 3; Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 8; Cycle 1 Days 9, 10; Pre-infusion, EOI on Cycle 2 Day 1; Pre-infusion on Cycle 3 Day 1; Cycle 3 Day 2; Pre-infusion on Cycle 4 Day 1; Pre-infusion on Cycle 5 Day 1; Cycle 5 Day 2; Pre-infusion on Day 1; Day 2 in Cycle 9 and then every 4 cycles for the first year followed by every 6 cycles; treatment discontinuation; 28 days after last dose; 3 months after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 1, 2; -4 hr for other timepoints) (infusion length = 2 hr) (1 cycle = 15 days)
Area Under the Serum Concentration-Time Curve (AUC) for RO6874281
Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 1; Cycle 1 Days 2, 3; Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 8; Cycle 1 Days 9, 10; Pre-infusion, EOI on Cycle 2 Day 1; Pre-infusion on Cycle 3 Day 1; Cycle 3 Day 2; Pre-infusion on Cycle 4 Day 1; Pre-infusion on Cycle 5 Day 1; Cycle 5 Day 2; Pre-infusion on Day 1; Day 2 in Cycle 9 and then every 4 cycles for the first year followed by every 6 cycles; treatment discontinuation; 28 days after last dose; 3 months after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 1, 2; -4 hr for other timepoints) (infusion length = 2 hr) (1 cycle = 15 days)
Maximum Observed Serum Concentration (Cmax) of RO6874281
Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 1; Cycle 1 Days 2, 3; Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 8; Cycle 1 Days 9, 10; Pre-infusion, EOI on Cycle 2 Day 1; Pre-infusion on Cycle 3 Day 1; Cycle 3 Day 2; Pre-infusion on Cycle 4 Day 1; Pre-infusion on Cycle 5 Day 1; Cycle 5 Day 2; Pre-infusion on Day 1; Day 2 in Cycle 9 and then every 4 cycles for the first year followed by every 6 cycles; treatment discontinuation; 28 days after last dose; 3 months after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 1, 2; -4 hr for other timepoints) (infusion length = 2 hr) (1 cycle = 15 days)
Serum Atezolizumab Concentration
Pre-infusion, 0.5 hr post EOI on Cycle 1 Day 1; Pre-infusion on Cycle 1 Day 8; Pre-infusion on Day 1 Cycles 2, 3, 4, 5, and 9 onwards; treatment discontinuation; 28, 120 days after last dose (up to 60 months) (Pre-infusion = -4 hr) (infusion length = 1 hr) (1 cycle = 15 days)
AUC of Atezolizumab
Pre-infusion, 0.5 hr post EOI on Cycle 1 Day 1; Pre-infusion on Cycle 1 Day 8; Pre-infusion on Day 1 Cycles 2, 3, 4, 5, and 9 onwards; treatment discontinuation; 28, 120 days after last dose (up to 60 months) (Pre-infusion = -4 hr) (infusion length = 1 hr) (1 cycle = 15 days)
Cmax of Atezolizumab
Pre-infusion, 0.5 hr post EOI on Cycle 1 Day 1; Pre-infusion on Cycle 1 Day 8; Pre-infusion on Day 1 Cycles 2, 3, 4, 5, and 9 onwards; treatment discontinuation; 28, 120 days after last dose (up to 60 months) (Pre-infusion = -4 hr) (infusion length = 1 hr) (1 cycle = 15 days)
Serum Bevacizumab Concentration
Pre-infusion, 0.5 hr post EOI on Cycle 2 Day 1; Pre-infusion on Cycle 2 Day 8; Pre-infusion on Day 1 Cycles 3, 4, 5, and 9 onwards; treatment discontinuation; 28 days after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 2, 3; -4 hr for other timepoints) (infusion length = 1.5 hr) (1 cycle = 15 days)
AUC of Bevacizumab
Pre-infusion, 0.5 hr post EOI on Cycle 2 Day 1; Pre-infusion on Cycle 2 Day 8; Pre-infusion on Day 1 Cycles 3, 4, 5, and 9 onwards; treatment discontinuation; 28 days after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 2, 3; -4 hr for other timepoints) (infusion length = 1.5 hr) (1 cycle = 15 days)
Cmax of Bevacizumab
Pre-infusion, 0.5 hr post EOI on Cycle 2 Day 1; Pre-infusion on Cycle 2 Day 8; Pre-infusion on Day 1 Cycles 3, 4, 5, and 9 onwards; treatment discontinuation; 28 days after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 2, 3; -4 hr for other timepoints) (infusion length = 1.5 hr) (1 cycle = 15 days)
Percentage of Participants with Anti-Drug Antibodies (ADA) to RO6874281
Baseline until 3 months post last dose of study treatment (assessed at pre-infusion on Days 1, 8 of Cycle 1; Pre-infusion on Day 1 of Cycles 2, 3, 4, 5, 9 and then every 4 cycles for the first year followed by every 6 cycles; treatment discontinuation; 28 days after last dose; 3 months after last dose [up to 60 months] [Pre-infusion = 0 hr for Day 1 Cycles 1, 2; -4 hr for other timepoints] [infusion length = 2 hr] [1 cycle = 15 days])
Absolute Lymphocytes Count in Peripheral Blood
At baseline; Day 1, 2 3, 8 of Cycle 4. Day 1, 2 of Cycle 5 and Cycle 6. Day 1 of Cycle 7, Cycle 8 and Subsequent Cycles; At treatment discontinuation; 28 days after last dose; 3 months after last dose
Density of Lymphocytes in Tumor Samples
Percentage of Participants with Programmed Death-Ligand 1 (PD-L1) Status in Tumor Samples
Percentage of Participants with CR as Determined by the Investigator Using RECIST v1.1
Percentage of Participants with Disease Control as Determined by the Investigator Using RECIST v1.1
Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1
Progression-Free Survival (PFS) as Determined by the Investigator Using RECIST v1.1
Overall Survival (OS)
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03063762
Brief Title
Study to Evaluate Safety, Pharmacokinetics and Therapeutic Activity of RO6874281 as a Combination Therapy in Participants With Unresectable Advanced and/or Metastatic Renal Cell Carcinoma (RCC)
Official Title
An Open-Label, Multi-Center, Randomized, Dose-Escalation, Phase 1b Study to Evaluate Safety, Pharmacokinetics and Therapeutic Activity of RO6874281 in Combination With Atezolizumab ± Bevacizumab in Patients With Unresectable Advanced and/or Metastatic Renal Cell Carcinoma
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
March 20, 2017 (Actual)
Primary Completion Date
June 14, 2021 (Actual)
Study Completion Date
June 14, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
This is an open-label, multi-center, randomized, Phase 1b, adaptive, clinical study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary therapeutic activity of RO6874281 in combination with atezolizumab with/without bevacizumab in participants with unresectable advanced and/or metastatic RCC. The study will consist of a dose-escalation part and an extension part.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Cell Carcinoma
Keywords
Renal Cell Carcinoma, RO6874281, Atezolizumab, Bevacizumab
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
69 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Escalation Part (Arm A): Atezolizumab, RO6874281
Arm Type
Experimental
Arm Description
Participants will receive RO6874281 in combination with atezolizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has complete response (CR), treatment may be discontinued and reintroduced if progressive disease (PD), for a maximum duration of 24 months.
Arm Title
Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Arm Type
Experimental
Arm Description
Participants will receive RO6874281 in combination with atezolizumab and bevacizumab until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Arm Title
Extension Part (Arm A): Atezolizumab, RO6874281
Arm Type
Experimental
Arm Description
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
Arm Title
Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281
Arm Type
Experimental
Arm Description
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once a week for 4 weeks followed by once every 2 weeks afterwards until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
Arm Title
Extension Part (Arm C): Atezolizumab, RO6874281
Arm Type
Experimental
Arm Description
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab once every 3 weeks until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: no new participants are being enrolled in the arm at this time.
Arm Title
Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281
Arm Type
Experimental
Arm Description
Based on the maximum tolerated dose or recommended dose as determined in the dose-escalation part, participants will receive RO6874281 in combination with atezolizumab and bevacizumab once every 3 weeks until disease progression, unacceptable toxicities, or withdrawal of consent, or as long as the participant experiences clinical benefit, or if the participant has CR, treatment may be discontinued and reintroduced if PD, for a maximum duration of 24 months.
Note: Arm D is closed for future enrollment
Intervention Type
Drug
Intervention Name(s)
Atezolizumab
Other Intervention Name(s)
Tecentriq®
Intervention Description
Arms A and B Atezolizumab will be administered at a dose of 840 milligrams (mg) prior to RO6874281 administration as an intravenous (IV) infusion on Days 1, 15, 29, and once in 2 weeks from Day 29 onwards. Doses in the extension part will be based on the maximum tolerated dose determined in the escalation part.
Arms C and D Atezolizumab will be administered at a dose of 1200mg as it is a Q3W schedule
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Other Intervention Name(s)
Avastin®
Intervention Description
Arms A and B Bevacizumab will be administered at a dose of 10 milligrams per kilogram (mg/kg) after the atezolizumab administration, and prior to RO6874281 administration as an IV infusion on Days 15, 29, and once in 2 weeks from Day 29 onwards.
In Arm D, Bevacizumab will be administered at a dose of 15mg/kg on Day 8 of Cycle 2 and on Day 8 of each consecutive cycle.
Intervention Type
Drug
Intervention Name(s)
RO6874281
Other Intervention Name(s)
simlukafusp alfa
Intervention Description
Arms A and B RO6874281 will be administered as an IV infusion on Days 1, 8, 15, 22, and 29, and once in 2 weeks from Day 29 onwards. Starting dose of RO6874281 will be 5 mg, and will be increased subsequently. Doses in the extension part will be based on the maximum tolerated dose determined in the escalation part.
In Arms C and D, RO will be administered on Q3W schedule at the dose defined in the dose escalation part
Primary Outcome Measure Information:
Title
Percentage of Participants with Dose-Limiting Toxicities (DLTs)
Description
The first patient in each cohort and regimen will be observed for safety for one week after the administration of RO6874281and atezolizumab +-bevacizumab, prior to enrollment of additional patients in a cohort.
The DLT will be counted for each dose separately and each patient will contribute one single representative data point.
Time Frame
Arm A: It ends one week after the second administration of RO6874281 + atezolizumab Arm B: one week after the first administration of RO6874281 + atezolizumab + bevacizumab
Title
Maximum Tolerated Dose (MTD) of RO6874281
Description
The MTD is defined as the highest dose with less than 33% probability of dose limiting toxicity (DLT).
Time Frame
Arm A: It ends one week after the second administration of RO6874281 + atezolizumab Arm B: one week after the first administration of RO6874281 + atezolizumab + bevacizumab
Title
Recommended Dose of RO6874281
Description
The recommended dose is defined as the lowest safe dose with the best likelihood for clinical benefit.
Time Frame
Arm A: It ends one week after the second administration of RO6874281 + atezolizumab Arm B: one week after the first administration of RO6874281 + atezolizumab + bevacizumab
Title
Percentage of Participants with Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
Description
Objective response rate (ORR) defined as the number of patients who achieved an objective response (partial response (PR) plus complete response (CR)) confirmed 28 or more days later, as determined by the Investigator using RECIST v1.1 and modified RECIST criteria at any time during the study divided by the number of response-evaluable patients.
Time Frame
Screening until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months)
Secondary Outcome Measure Information:
Title
Serum RO6874281 Concentration
Description
Pre-infusion, 1 hour (hr) post start of infusion, end of infusion (EOI), 2, 6 hr post EOI on Cycle 1 Day 1; Cycle 1 Days 2, 3; Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 8; Cycle 1 Days 9, 10; Pre-infusion, EOI on Cycle 2 Day 1; Pre-infusion on Cycle 3 Day 1; Cycle 3 Day 2; Pre-infusion on Cycle 4 Day 1; Pre-infusion on Cycle 5 Day 1; Cycle 5 Day 2; Pre-infusion on Day 1; Day 2 in Cycle 9 and then every 4 cycles for the first year followed by every 6 cycles; treatment discontinuation; 28 days after last dose; 3 months after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 1, 2; -4 hr for other timepoints) (infusion length = 2 hr) (1 cycle = 15 days)
Time Frame
Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Title
Area Under the Serum Concentration-Time Curve (AUC) for RO6874281
Description
Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 1; Cycle 1 Days 2, 3; Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 8; Cycle 1 Days 9, 10; Pre-infusion, EOI on Cycle 2 Day 1; Pre-infusion on Cycle 3 Day 1; Cycle 3 Day 2; Pre-infusion on Cycle 4 Day 1; Pre-infusion on Cycle 5 Day 1; Cycle 5 Day 2; Pre-infusion on Day 1; Day 2 in Cycle 9 and then every 4 cycles for the first year followed by every 6 cycles; treatment discontinuation; 28 days after last dose; 3 months after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 1, 2; -4 hr for other timepoints) (infusion length = 2 hr) (1 cycle = 15 days)
Time Frame
Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Title
Maximum Observed Serum Concentration (Cmax) of RO6874281
Description
Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 1; Cycle 1 Days 2, 3; Pre-infusion, 1 hr post start of infusion, EOI, 2, 6 hr post EOI on Cycle 1 Day 8; Cycle 1 Days 9, 10; Pre-infusion, EOI on Cycle 2 Day 1; Pre-infusion on Cycle 3 Day 1; Cycle 3 Day 2; Pre-infusion on Cycle 4 Day 1; Pre-infusion on Cycle 5 Day 1; Cycle 5 Day 2; Pre-infusion on Day 1; Day 2 in Cycle 9 and then every 4 cycles for the first year followed by every 6 cycles; treatment discontinuation; 28 days after last dose; 3 months after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 1, 2; -4 hr for other timepoints) (infusion length = 2 hr) (1 cycle = 15 days)
Time Frame
Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Title
Serum Atezolizumab Concentration
Description
Pre-infusion, 0.5 hr post EOI on Cycle 1 Day 1; Pre-infusion on Cycle 1 Day 8; Pre-infusion on Day 1 Cycles 2, 3, 4, 5, and 9 onwards; treatment discontinuation; 28, 120 days after last dose (up to 60 months) (Pre-infusion = -4 hr) (infusion length = 1 hr) (1 cycle = 15 days)
Time Frame
Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Title
AUC of Atezolizumab
Description
Pre-infusion, 0.5 hr post EOI on Cycle 1 Day 1; Pre-infusion on Cycle 1 Day 8; Pre-infusion on Day 1 Cycles 2, 3, 4, 5, and 9 onwards; treatment discontinuation; 28, 120 days after last dose (up to 60 months) (Pre-infusion = -4 hr) (infusion length = 1 hr) (1 cycle = 15 days)
Time Frame
Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Title
Cmax of Atezolizumab
Description
Pre-infusion, 0.5 hr post EOI on Cycle 1 Day 1; Pre-infusion on Cycle 1 Day 8; Pre-infusion on Day 1 Cycles 2, 3, 4, 5, and 9 onwards; treatment discontinuation; 28, 120 days after last dose (up to 60 months) (Pre-infusion = -4 hr) (infusion length = 1 hr) (1 cycle = 15 days)
Time Frame
Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Title
Serum Bevacizumab Concentration
Description
Pre-infusion, 0.5 hr post EOI on Cycle 2 Day 1; Pre-infusion on Cycle 2 Day 8; Pre-infusion on Day 1 Cycles 3, 4, 5, and 9 onwards; treatment discontinuation; 28 days after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 2, 3; -4 hr for other timepoints) (infusion length = 1.5 hr) (1 cycle = 15 days)
Time Frame
Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Title
AUC of Bevacizumab
Description
Pre-infusion, 0.5 hr post EOI on Cycle 2 Day 1; Pre-infusion on Cycle 2 Day 8; Pre-infusion on Day 1 Cycles 3, 4, 5, and 9 onwards; treatment discontinuation; 28 days after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 2, 3; -4 hr for other timepoints) (infusion length = 1.5 hr) (1 cycle = 15 days)
Time Frame
Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Title
Cmax of Bevacizumab
Description
Pre-infusion, 0.5 hr post EOI on Cycle 2 Day 1; Pre-infusion on Cycle 2 Day 8; Pre-infusion on Day 1 Cycles 3, 4, 5, and 9 onwards; treatment discontinuation; 28 days after last dose (up to 60 months) (Pre-infusion = 0 hr for Day 1 Cycles 2, 3; -4 hr for other timepoints) (infusion length = 1.5 hr) (1 cycle = 15 days)
Time Frame
Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Title
Percentage of Participants with Anti-Drug Antibodies (ADA) to RO6874281
Description
Baseline until 3 months post last dose of study treatment (assessed at pre-infusion on Days 1, 8 of Cycle 1; Pre-infusion on Day 1 of Cycles 2, 3, 4, 5, 9 and then every 4 cycles for the first year followed by every 6 cycles; treatment discontinuation; 28 days after last dose; 3 months after last dose [up to 60 months] [Pre-infusion = 0 hr for Day 1 Cycles 1, 2; -4 hr for other timepoints] [infusion length = 2 hr] [1 cycle = 15 days])
Time Frame
Baseline until 3 months post last dose of study treatment (detailed timeframe is provided in outcome measure description)
Title
Absolute Lymphocytes Count in Peripheral Blood
Description
At baseline; Day 1, 2 3, 8 of Cycle 4. Day 1, 2 of Cycle 5 and Cycle 6. Day 1 of Cycle 7, Cycle 8 and Subsequent Cycles; At treatment discontinuation; 28 days after last dose; 3 months after last dose
Time Frame
Screening until 120 days post last dose of study treatment (up to 60 months)
Title
Density of Lymphocytes in Tumor Samples
Time Frame
Archival biopsy: Baseline; Fresh biopsies: Baseline, Day 8 of Cycle 4; Optional biopsies: Any time during the study conduct (1 cycle = 15 days) (up to 60 months)
Title
Percentage of Participants with Programmed Death-Ligand 1 (PD-L1) Status in Tumor Samples
Time Frame
Archival biopsy: Baseline; Fresh biopsies: Baseline, Day 8 of Cycle 4; Optional biopsies: Any time during the study conduct (1 cycle = 15 days) (up to 60 months)
Title
Percentage of Participants with CR as Determined by the Investigator Using RECIST v1.1
Time Frame
Screening until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months)
Title
Percentage of Participants with Disease Control as Determined by the Investigator Using RECIST v1.1
Time Frame
Screening until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months)
Title
Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1
Time Frame
Screening until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months)
Title
Progression-Free Survival (PFS) as Determined by the Investigator Using RECIST v1.1
Time Frame
From randomization until disease progression or study treatment discontinuation (assessed at every 8 weeks after study treatment start for the first year, and every 12 weeks thereafter, up to 24 months)
Title
Overall Survival (OS)
Time Frame
From randomization until death (up to 60 months)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria:
Unresectable advanced and/or metastatic RCC with component of clear cell histology and/or component of sarcomatoid histology that has not been previously treated with any systemic therapy, including treatment in the adjuvant setting
During dose escalation only, an additional population with unresectable advanced and/or metastatic 2nd line RCC patients is allowed
At least one tumor lesion with location accessible to biopsy per clinical judgment of the treating physician
Consent to provide an archival tumor tissue sample (if available) and to undergo baseline and on treatment tumor biopsies for pharmacodynamic biomarker analysis
Measurable disease, as defined by RECIST v1.1. At least one lesion accessible for biopsy
Participants with unilateral pleural effusion are eligible if they fulfill both of the following: (a) New York Heart Association (NYHA) Class 1; (b) Global initiative for obstructive lung disease (GOLD) test level 1 (forced expiratory volume in 1 second [FEV1]/ forced vital capacity [FVC] less than [<] 0.7 and FEV1 greater than or equal to [>=] 80 percent [%] predicted after inhaled bronchodilator)
Adequate hematological function: neutrophil count of ≥1.5 ≥109 cells/L, platelet count of ≥100,000/≥L, Hb ≥9 g/dL (5.6 mmol/L), lymphocytes ≥0.8 ≥109 cells/L.
Exclusion Criteria:
Symptomatic or untreated central nervous system (CNS) metastases
Participants with asymptomatic CNS metastases with previous or concomitant brain deficiencies, as defined in the protocol
Participants with confirmed bilateral pleural effusion
Episode of significant cardiovascular/cerebrovascular acute disease within 6 months prior to Cycle 1 Day 1
Active or uncontrolled infections
Human immunodeficiency virus (HIV) or active Hepatitis A, B, C, D and E virus (HAV, HBV, HCV, HDV and HEV) infection.
Major surgery or significant traumatic injury <28 days prior to Cycle 1 Day 1 (excluding fine needle biopsies) or anticipation of the need for major surgery during study treatment
Serious, non-healing wound; active ulcer; or untreated bone fracture
Proteinuria as demonstrated by a urine protein to creatinine ratio (UPCR) of >=1.0 at screening
History of, active or suspicion of autoimmune disease
Concurrent use of high dose of systemic steroids. The use of inhaled, topical and ophthalmic steroids is allowed.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
Facility Name
Yale Cancer Center; Medical Oncology
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Facility Name
Northwestern Center for Clinical Research; Cancer Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Maryland Greenebaum Comprehensive Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Princess Margaret Cancer Center
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1Z5
Country
Canada
Facility Name
Herlev Hospital; Afdeling for Kræftbehandling
City
Herlev
ZIP/Postal Code
2730
Country
Denmark
Facility Name
Centre Léon Bérard - Centre régional de lutte contre le cancer Rhône-Alpes
City
Lyon
ZIP/Postal Code
69008
Country
France
Facility Name
Institut Claudius Regaud; Departement Oncologie Medicale
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
Universitätsklinikum Tübingen; Klinik für Urologie
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Uniklinikum, Comprehensive Cancer Center Mainfranken; Interdisziplinäres Studienzentrum mit ECTU
City
Würzburg
ZIP/Postal Code
97078
Country
Germany
Facility Name
Universita di Modena e Reggio Emilia;Dipartimento di Oncologia ed Ematologia
City
Modena
State/Province
Emilia-Romagna
ZIP/Postal Code
41100
Country
Italy
Facility Name
Fondazione IRCCS Policlinico San Matteo, Oncologia
City
Pavia
State/Province
Lombardia
ZIP/Postal Code
27100
Country
Italy
Facility Name
Asan Medical Center
City
Seoul
ZIP/Postal Code
05505
Country
Korea, Republic of
Facility Name
Samsung Medical Center
City
Seoul
ZIP/Postal Code
135-710
Country
Korea, Republic of
Facility Name
Clinica Universitaria de Navarra; Servicio de Oncologia
City
Pamplona
State/Province
Navarra
ZIP/Postal Code
31008
Country
Spain
Facility Name
Hospital del Mar; Servicio de Oncologia
City
Barcelona
ZIP/Postal Code
08003
Country
Spain
Facility Name
Hospital Univ Vall d'Hebron; Servicio de Oncologia
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Clínic i Provincial; Servicio de Oncología
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital Ramon y Cajal; Servicio de Oncologia
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
START Madrid-FJD, Hospital Fundacion Jimenez Diaz
City
Madrid
ZIP/Postal Code
28040
Country
Spain
Facility Name
Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
City
Valencia
ZIP/Postal Code
46010
Country
Spain
Facility Name
Barts & London School of Med; Medical Oncology
City
London
ZIP/Postal Code
EC1A 7BE
Country
United Kingdom
Facility Name
The Christie
City
Manchester
ZIP/Postal Code
M20 4BX
Country
United Kingdom
Facility Name
Southampton General Hospital; Medical Oncology
City
Southampton
ZIP/Postal Code
SO16 6YD
Country
United Kingdom
12. IPD Sharing Statement
Learn more about this trial
Study to Evaluate Safety, Pharmacokinetics and Therapeutic Activity of RO6874281 as a Combination Therapy in Participants With Unresectable Advanced and/or Metastatic Renal Cell Carcinoma (RCC)
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