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)

Renal Cell Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03063762
• Other study ID #: BP39365
• Secondary ID: 2016-003528-22
• Status: Completed
• Phase: Phase 1
• Start date: March 20, 2017
• Est. completion date: June 14, 2021

Study information

• Verified date: February 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 69
• Est. completion date: June 14, 2021
• Est. primary completion date: June 14, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Renal Cell Carcinoma

Intervention

Drug:
• Atezolizumab
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
• Bevacizumab
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.
• RO6874281
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

Locations

Country	Name	City	State
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Denmark	Herlev Hospital; Afdeling for Kræftbehandling	Herlev
France	Centre Léon Bérard - Centre régional de lutte contre le cancer Rhône-Alpes	Lyon
France	Institut Claudius Regaud; Departement Oncologie Medicale	Toulouse
Germany	Universitätsklinikum Tübingen; Klinik für Urologie	Tübingen
Germany	Uniklinikum, Comprehensive Cancer Center Mainfranken; Interdisziplinäres Studienzentrum mit ECTU	Würzburg
Italy	Universita di Modena e Reggio Emilia;Dipartimento di Oncologia ed Ematologia	Modena	Emilia-Romagna
Italy	Fondazione IRCCS Policlinico San Matteo, Oncologia	Pavia	Lombardia
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Spain	Hospital Clínic i Provincial; Servicio de Oncología	Barcelona
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid
Spain	START Madrid-FJD, Hospital Fundacion Jimenez Diaz	Madrid
Spain	Clinica Universitaria de Navarra; Servicio de Oncologia	Pamplona	Navarra
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia
United Kingdom	Barts & London School of Med; Medical Oncology	London
United Kingdom	The Christie	Manchester
United Kingdom	Southampton General Hospital; Medical Oncology	Southampton
United States	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

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  France,  Germany,  Italy,  Korea, Republic of,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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
Primary	Maximum Tolerated Dose (MTD) of RO6874281	The MTD is defined as the highest dose with less than 33% probability of dose limiting toxicity (DLT).	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
Primary	Recommended Dose of RO6874281	The recommended dose is defined as the lowest safe dose with the best likelihood for clinical benefit.	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
Primary	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.	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	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)	Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Secondary	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)	Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Secondary	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)	Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Secondary	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)	Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Secondary	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)	Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Secondary	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)	Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Secondary	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)	Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Secondary	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)	Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Secondary	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)	Pre-infusion on Cycle 2 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)
Secondary	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])	Baseline until 3 months post last dose of study treatment (detailed timeframe is provided in outcome measure description)
Secondary	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	Screening until 120 days post last dose of study treatment (up to 60 months)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	Overall Survival (OS)		From randomization until death (up to 60 months)