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)

Roche

Status and phase: Completed; Phase 1

Conditions: Renal Cell Carcinoma

Treatments: Drug: RO6874281; Drug: Atezolizumab; Drug: Bevacizumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT03063762

BP39365

2016-003528-22 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 69 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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69 participants in 6 patient groups

Escalation Part (Arm A): Atezolizumab, RO6874281

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab

Drug: RO6874281

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

Experimental group

Description:

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.

Treatment:

Drug: Bevacizumab

Drug: Atezolizumab

Drug: RO6874281

Extension Part (Arm A): Atezolizumab, RO6874281

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab

Drug: RO6874281

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

Experimental group

Description:

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.

Treatment:

Drug: Bevacizumab

Drug: Atezolizumab

Drug: RO6874281

Extension Part (Arm C): Atezolizumab, RO6874281

Experimental group

Description:

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.

Treatment:

Drug: Atezolizumab

Drug: RO6874281

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

Experimental group

Description:

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

Treatment:

Drug: Bevacizumab

Drug: Atezolizumab

Drug: RO6874281