A Study of Atezolizumab in Combination With Cabozantinib Compared to Cabozantinib Alone in Participants With Advanced Renal Cell Carcinoma After Immune Checkpoint Inhibitor Treatment

Study Overview
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Brief Summary
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This is a Phase III, multicenter, randomized, open-label study designed to evaluate the efficacy and safety of atezolizumab given in combination with cabozantinib versus cabozantinib alone in participants with inoperable, locally advanced, or metastatic renal cell carcinoma (RCC) who experienced radiographic tumor progression during or after Immune Checkpoint Inhibitor (ICI) treatment in the metastatic setting.

Official Title
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A Phase III, Multicenter, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Atezolizumab Given in Combination With Cabozantinib Versus Cabozantinib Alone in Patients With Inoperable, Locally Advanced, or Metastatic Renal Cell Carcinoma Who Experienced Radiographic Tumor Progression During or After Immune Checkpoint Inhibitor Treatment

Conditions
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Carcinoma, Renal Cell

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed locally advanced or metastatic clear cell or non-clear cell (papillary, chromophobe, and unclassified only) RCC. RCC with sarcomatoid features is allowed. Patients with the chromophobe subtype of non-clear cell RCC must have sarcomatoid differentiation. Radiographic disease progression to prior ICI therapy for RCC. Patients who experienced radiographic tumor progression during or within 6 months after the last dose of adjuvant ICI are also eligible. ICI is defined by anti-PD-L1 or anti-PD1 antibody including atezolizumab, avelumab, pembrolizumab, durvalumab, or nivolumab. Only patients for whom the immediate preceding line of therapy was an ICI are allowed. Measurable disease per RECIST v1.1 Evaluable IMDC risk score Archival tumor specimen, and pretreatment tumor tissue from fresh biopsy at screening, if clinically feasible. Both archival and fresh samples are preferred. KPS score of >=70 Recovery to baseline or Grade </= 1 NCI CTCAE v5.0 from toxicities related to any prior treatments, unless adverse events are clinically nonsignificant and/or stable in the opinion of the investigator. Grade 2 alopecia is allowed for study participation Adequate hematologic and end-organ function Negative HIV test at screening Negative hepatitis B testing at screening Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm Exclusion Criteria: Treatment with anti-cancer therapy within 14 days prior to initiation of study treatment Patients received cabozantinib at any time prior to screening Patients who received more than one ICI treatment in the locally advanced or metastatic setting Patients who received more than two prior lines of therapy in the locally advanced or metastatic setting Patients who have received a mammalian target of rapamycin (mTOR) inhibitor in any setting Symptomatic, untreated, or actively progressing CNS metastases History of leptomeningeal disease Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures Uncontrolled or symptomatic hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab History of malignancy other than renal carcinoma within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death Radiotherapy for RCC within 14 days prior to Day 1 of Cycle 1 Active tuberculosis Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after final dose of atezolizumab and 4 months after final dose of cabozantinib Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that, in the opinion of the investigator, could impact patient safety Pharmacologically uncompensated, symptomatic hypothyroidism Uncontrolled hypertension defined as sustained blood pressure >150 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment (all countries except France); sustained BP > 140 mmHg systolic or > 90 mmHg diastolic despite optimal antihypertensive treatment (France only) Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, unstable arrhythmia, or unstable angina) within 3 months prior to initiation of study treatment Significant vascular disease (e.g., aortic aneurysm or arterial dissection requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of Cycle 1 History of congenital QT syndrome History or presence of an abnormal ECG that is clinically significant in the investigator's opinion Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitor dabigatran, direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g. clopidogrel)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezo+Cabo<br>Participants will receive atezolizumab every 3 weeks on Day 1 of each 21-day cycle (1 cycle=21 days) plus oral tablets of cabozantinib every day. | Drug: Atezolizumab<br>* Atezolizumab 1200 mg will be administered at a fixed dose on Day 1 of each 21-day cycle by IV infusion every 3 weeks.<br>* Other names: Tecentriq;Drug: Cabozantinib<br>* Cabozantinib 60 mg (three 20-mg tablets) administered orally once daily.<br>* Other names: Cabometyx;|
| Active Comparator: Cabozantinib<br>Participants will receive cabozantinib every day. | Drug: Cabozantinib<br>* Cabozantinib 60 mg (three 20-mg tablets) administered orally once daily.<br>* Other names: Cabometyx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS), as assessed by Independent Review Facility (IRF) | Progression-free survival (PFS), defined as the time from randomization to the first occurrence of disease progression according to RECIST v1.1, as assessed by Independent Review Facility (IRF-PFS) or death from any cause, whichever occurs first. | Randomization up to approximately 27 months | 
| Overall survival (OS) | Overall survival (OS), defined as the time from randomization to death from any cause. | Randomization up to approximately 52 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS Assessed by the Investigators (INV-PFS) | PFS assessed by the investigators (INV-PFS), defined as the time from randomization to the first occurrence of disease progression according to RECIST v1.1 or death from any cause (whichever occurs first). | Randomization up to approximately 27 months | 
| Investigator Assessed Objective Response Rate (INV-ORR) | INV-ORR, defined as the proportion of patients with a complete response (CR) or partial response (PR) on two consecutive occasions at least 4 weeks apart according to RECIST v1.1. | Randomization up to approximately 27 months | 
| IRF Assessed Objective Response Rate (IRF-ORR) | IRF-ORR, defined as the proportion of patients with a complete response (CR) or partial response (PR) on two consecutive occasions at least 4 weeks apart according to RECIST v1.1. | Randomization up to approximately 27 months | 
| Investigator Assessed Duration of Objective Response (INV-DOR) | INV-DOR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first) according to RECIST v1.1. | Randomization up to approximately 27 months | 
| IRF Assessed DOR (IRF-DOR) | IRF-DOR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first) according to RECIST v1.1. | Randomization up to approximately 27 months | 
| Percentage of Participants With Adverse Events |  | Randomization up to approximately 27 months | 
| Atezolizumab Concentrations |  | At pre-defined intervals from first administration of study drug up to approximately 27 months | 
| Cabozantinib Concentrations |  | At pre-defined intervals from first administration of study drug up to approximately 27 months | 
| Prevalence of Anti-Drug Antibodies (ADAs) to Atezolizumab |  | Baseline | 
| Incidence of ADAs to Atezolizumab During the Study |  | At pre-defined intervals from first administration of study drug up to approximately 27 months |