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)
- Conditions
- Renal Cell Carcinoma
- Interventions
- Registration Number
- NCT03063762
- Lead Sponsor
- Hoffmann-La Roche
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 69
Not provided
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Extension Part (Arm C): Atezolizumab, RO6874281 RO6874281 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. Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281 Atezolizumab 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 Escalation Part (Arm A): Atezolizumab, RO6874281 Atezolizumab 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. Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281 Bevacizumab 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. Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281 Atezolizumab 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. Extension Part (Arm A): Atezolizumab, RO6874281 Atezolizumab 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. Extension Part (Arm A): Atezolizumab, RO6874281 RO6874281 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. Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281 Atezolizumab 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. Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281 Bevacizumab 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. Extension Part (Arm C): Atezolizumab, RO6874281 Atezolizumab 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. Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281 Bevacizumab 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 Escalation Part (Arm A): Atezolizumab, RO6874281 RO6874281 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. Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281 RO6874281 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. Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281 RO6874281 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. Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281 RO6874281 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
- Primary Outcome Measures
Name Time Method Percentage of Participants with Dose-Limiting Toxicities (DLTs) 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 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.Recommended Dose of RO6874281 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 The recommended dose is defined as the lowest safe dose with the best likelihood for clinical benefit.
Maximum Tolerated Dose (MTD) of RO6874281 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 The MTD is defined as the highest dose with less than 33% probability of dose limiting toxicity (DLT).
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) 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) 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
Name Time Method Area Under the Serum Concentration-Time Curve (AUC) for RO6874281 Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure 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)
Cmax of Atezolizumab Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure 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)
AUC of Bevacizumab Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure 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)
Serum Atezolizumab Concentration Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure 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)
Serum RO6874281 Concentration Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure 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)
Maximum Observed Serum Concentration (Cmax) of RO6874281 Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure 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)
Cmax of Bevacizumab Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure 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)
AUC of Atezolizumab Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure 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)
Serum Bevacizumab Concentration Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure 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)
Density of Lymphocytes in Tumor Samples 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) Percentage of Participants with Programmed Death-Ligand 1 (PD-L1) Status in Tumor Samples 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) Percentage of Participants with CR as Determined by the Investigator Using RECIST v1.1 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) Absolute Lymphocytes Count in Peripheral Blood Screening until 120 days post last dose of study treatment (up to 60 months) 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
Percentage of Participants with Disease Control as Determined by the Investigator Using RECIST v1.1 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) Percentage of Participants with Anti-Drug Antibodies (ADA) to RO6874281 Baseline until 3 months post last dose of study treatment (detailed timeframe is provided in outcome measure 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 \[up to 60 months\] \[Pre-infusion = 0 hr for Day 1 Cycles 1, 2; -4 hr for other timepoints\] \[infusion length = 2 hr\] \[1 cycle = 15 days\])
Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1 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) Progression-Free Survival (PFS) as Determined by the Investigator Using RECIST v1.1 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) Overall Survival (OS) From randomization until death (up to 60 months)
Trial Locations
- Locations (23)
Princess Margaret Cancer Center
🇨🇦Toronto, Ontario, Canada
Centre Léon Bérard - Centre régional de lutte contre le cancer Rhône-Alpes
🇫🇷Lyon, France
Universita di Modena e Reggio Emilia;Dipartimento di Oncologia ed Ematologia
🇮🇹Modena, Emilia-Romagna, Italy
Hospital Ramon y Cajal; Servicio de Oncologia
🇪🇸Madrid, Spain
University of Maryland Greenebaum Comprehensive Cancer Center
🇺🇸Baltimore, Maryland, United States
Northwestern Center for Clinical Research; Cancer Center
🇺🇸Chicago, Illinois, United States
Yale Cancer Center; Medical Oncology
🇺🇸New Haven, Connecticut, United States
Herlev Hospital; Afdeling for Kræftbehandling
🇩🇰Herlev, Denmark
Institut Claudius Regaud; Departement Oncologie Medicale
🇫🇷Toulouse, France
Universitätsklinikum Tübingen; Klinik für Urologie
🇩🇪Tübingen, Germany
Uniklinikum, Comprehensive Cancer Center Mainfranken; Interdisziplinäres Studienzentrum mit ECTU
🇩🇪Würzburg, Germany
Fondazione IRCCS Policlinico San Matteo, Oncologia
🇮🇹Pavia, Lombardia, Italy
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Hospital del Mar; Servicio de Oncologia
🇪🇸Barcelona, Spain
Hospital ClÃnic i Provincial; Servicio de OncologÃa
🇪🇸Barcelona, Spain
Hospital Univ Vall d'Hebron; Servicio de Oncologia
🇪🇸Barcelona, Spain
Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
🇪🇸Valencia, Spain
START Madrid-FJD, Hospital Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Barts & London School of Med; Medical Oncology
🇬🇧London, United Kingdom
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Clinica Universitaria de Navarra; Servicio de Oncologia
🇪🇸Pamplona, Navarra, Spain
Southampton General Hospital; Medical Oncology
🇬🇧Southampton, United Kingdom
The Christie
🇬🇧Manchester, United Kingdom