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)

Hoffmann-La Roche69 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Renal Cell Carcinoma

Interventions

AtezolizumabDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (23)

Yale Cancer Center; Medical Oncology

New Haven, Connecticut, United States

Northwestern Center for Clinical Research; Cancer Center

Chicago, Illinois, United States

University of Maryland Greenebaum Comprehensive Cancer Center

Baltimore, Maryland, United States

Princess Margaret Cancer Center

Toronto, Ontario, Canada

Herlev Hospital; Afdeling for Kræftbehandling

Herlev, Denmark

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

Lyon, France

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

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

Modena, Emilia-Romagna, Italy

...and 13 more locations

Outcomes

Primary Outcomes

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.

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

Maximum Tolerated Dose (MTD) of RO6874281

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

Recommended Dose of RO6874281

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

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.

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 Outcomes

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)