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)

NCT03063762 | Completed Phase 1 FDA Drug

• 2 other identifiers: BP393652016-003528-22
• Study Type: interventional
• Target: 69
• Locations: 9 countries
• Sites: 23

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.

Conditions

Renal Cell Carcinoma

Keywords

Renal Cell Carcinoma; RO6874281; Atezolizumab; Bevacizumab

Outcome Measures

Primary Outcomes (4)

• 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

• 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

• 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

• 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 Outcomes (18)

• Serum RO6874281 Concentration

  Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)

• 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)

• 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)

• Serum Atezolizumab Concentration

  Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)

• AUC of Atezolizumab

  Pre-infusion on Cycle 1 Day 1 up to 60 months (detailed timeframe is provided in outcome measure description)

Study Arms (6)

Escalation Part (Arm A): Atezolizumab, RO6874281

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: RO6874281

Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Bevacizumab; Drug: RO6874281

Extension Part (Arm A): Atezolizumab, RO6874281

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: RO6874281

Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Bevacizumab; Drug: RO6874281

Extension Part (Arm C): Atezolizumab, RO6874281

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: RO6874281

Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281

EXPERIMENTAL

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

Drug: Atezolizumab; Drug: Bevacizumab; Drug: RO6874281

Interventions

Atezolizumab DRUG

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

Also known as: Tecentriq®

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

Bevacizumab DRUG

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.

Also known as: Avastin®

Escalation Part (Arm B): Atezolizumab, Bevacizumab, RO6874281; Extension Part (Arm B): Atezolizumab, Bevacizumab, RO6874281; Extension Part (Arm D): Atezolizumab, Bevacizumab, RO6874281

RO6874281 DRUG

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

Also known as: simlukafusp alfa

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (23)

Yale Cancer Center; Medical Oncology

New Haven, Connecticut, 06520, United States

Location

Northwestern Center for Clinical Research; Cancer Center

Chicago, Illinois, 60611, United States

Location

University of Maryland Greenebaum Comprehensive Cancer Center

Baltimore, Maryland, 21201, United States

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 1Z5, Canada

Location

Herlev Hospital; Afdeling for Kræftbehandling

Herlev, 2730, Denmark

Location

Centre Léon Bérard - Centre régional de lutte contre le cancer Rhône-Alpes

Lyon, 69008, France

Location

Institut Claudius Regaud; Departement Oncologie Medicale

Toulouse, 31059, France

Location

Universitätsklinikum Tübingen; Klinik für Urologie

Tübingen, 72076, Germany

Location

Uniklinikum, Comprehensive Cancer Center Mainfranken; Interdisziplinäres Studienzentrum mit ECTU

Würzburg, 97078, Germany

Location

Universita di Modena e Reggio Emilia;Dipartimento di Oncologia ed Ematologia

Modena, Emilia-Romagna, 41100, Italy

Location

Fondazione IRCCS Policlinico San Matteo, Oncologia

Pavia, Lombardy, 27100, Italy

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 135-710, South Korea

Location

Clinica Universitaria de Navarra; Servicio de Oncologia

Pamplona, Navarre, 31008, Spain

Location

Hospital del Mar; Servicio de Oncologia

Barcelona, 08003, Spain

Location

Hospital Univ Vall d'Hebron; Servicio de Oncologia

Barcelona, 08035, Spain

Location

Hospital Clínic i Provincial; Servicio de Oncología

Barcelona, 08036, Spain

Location

Hospital Ramon y Cajal; Servicio de Oncologia

Madrid, 28034, Spain

Location

START Madrid-FJD, Hospital Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia

Valencia, 46010, Spain

Location

Barts & London School of Med; Medical Oncology

London, EC1A 7BE, United Kingdom

Location

The Christie

Manchester, M20 4BX, United Kingdom

Location

Southampton General Hospital; Medical Oncology

Southampton, SO16 6YD, United Kingdom

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

atezolizumab; Bevacizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2017
• First Posted: February 24, 2017
• Study Start: March 20, 2017
• Primary Completion: June 14, 2021
• Study Completion: June 14, 2021
• Last Updated: February 17, 2023

Record last verified: 2023-02

Locations

US (3); CA (1); DE (2); IT (2); GB (3); ES (7); KR (2); DK (1); FR (2)