Clinical trial NCT03063762: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Cell Carcinoma
Keywords: Renal Cell Carcinoma
RO6874281
Atezolizumab
Bevacizumab
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2017-02-24
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Percentage of Participants with Dose-Limiting Toxicities (DLTs)
timeFrame: 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
measure: Maximum Tolerated Dose (MTD) of RO6874281
timeFrame: 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
measure: Recommended Dose of RO6874281
timeFrame: 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
measure: 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)
timeFrame: 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 outcomes:
measure: Serum RO6874281 Concentration
timeFrame: Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
measure: Area Under the Serum Concentration-Time Curve (AUC) for RO6874281
timeFrame: Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
measure: Maximum Observed Serum Concentration (Cmax) of RO6874281
timeFrame: Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
measure: Serum Atezolizumab Concentration
timeFrame: Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
measure: AUC of Atezolizumab
timeFrame: Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
measure: Cmax of Atezolizumab
timeFrame: Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
measure: Serum Bevacizumab Concentration
timeFrame: Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
measure: AUC of Bevacizumab
timeFrame: Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
measure: Cmax of Bevacizumab
timeFrame: Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
measure: Percentage of Participants with Anti-Drug Antibodies (ADA) to RO6874281
timeFrame: Baseline until 3 months post last dose of study treatment (detailed timeframe is provided in outcome measure description)
measure: Absolute Lymphocytes Count in Peripheral Blood
timeFrame: Screening until 120 days post last dose of study treatment (up to 60 months)
measure: Density of Lymphocytes in Tumor Samples
timeFrame: 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)
measure: Percentage of Participants with Programmed Death-Ligand 1 (PD-L1) Status in Tumor Samples
timeFrame: 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)
measure: Percentage of Participants with CR as Determined by the Investigator Using RECIST v1.1
timeFrame: 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)
measure: Percentage of Participants with Disease Control as Determined by the Investigator Using RECIST v1.1
timeFrame: 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)
measure: Duration of Response (DOR) as Determined by the Investigator Using RECIST v1.1
timeFrame: 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)
measure: Progression-Free Survival (PFS) as Determined by the Investigator Using RECIST v1.1
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: From randomization until death (up to 60 months)
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Cancer Center; Medical Oncology
state: Connecticut
city: Chicago
country: United States
facility: Northwestern Center for Clinical Research; Cancer Center
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Comprehensive Cancer Center
state: Maryland
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Herlev
country: Denmark
facility: Herlev Hospital; Afdeling for Kræftbehandling
city: Lyon
country: France
facility: Centre Léon Bérard - Centre régional de lutte contre le cancer Rhône-Alpes
city: Toulouse
country: France
facility: Institut Claudius Regaud; Departement Oncologie Medicale
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen; Klinik für Urologie
city: Würzburg
country: Germany
facility: Uniklinikum, Comprehensive Cancer Center Mainfranken; Interdisziplinäres Studienzentrum mit ECTU
city: Modena
country: Italy
facility: Universita di Modena e Reggio Emilia;Dipartimento di Oncologia ed Ematologia
state: Emilia-Romagna
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo, Oncologia
state: Lombardia
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra; Servicio de Oncologia
state: Navarra
city: Barcelona
country: Spain
facility: Hospital del Mar; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial; Servicio de Oncología
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal; Servicio de Oncologia
city: Madrid
country: Spain
facility: START Madrid-FJD, Hospital Fundacion Jimenez Diaz
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
city: London
country: United Kingdom
facility: Barts & London School of Med; Medical Oncology
city: Manchester
country: United Kingdom
facility: The Christie
city: Southampton
country: United Kingdom
facility: Southampton General Hospital; Medical Oncology
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: