NCT04338269 - A Study of Atezolizumab in Combination With Cabozantinib Compared to Cabozantinib Alone in Participants With Advanced Renal Cell Carcinoma After Immune Checkpoint Inhibitor Treatment | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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)

Outcomes

Primary Outcomes

Progression Free Survival (PFS) as Assessed by an Independent Review Facility (IRF) (IRF-PFS) According to RECIST v1.1

PFS was defined as the time from randomization to the first occurrence to PD, as determined by the IRF per RECIST v1.1, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters (SOD) of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 millimeters (mm). Data for participants who did not experience PD or death was censored at the last tumor assessment date. Data for participants with no post-baseline tumor assessments was censored at the randomization date. PFS was estimated using Kaplan-Meier (KM) method.

Time frame: From randomization to the first occurrence of PD according to RECIST v1.1, or death from any cause, whichever occurred first (up to 2 years 5 months)

Overall Survival (OS)

OS was defined as the time from randomization to death due to any cause. Data for participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants without post-baseline information were censored at the date of randomization. OS was estimated using KM method.

Time frame: From randomization to death due to any cause (up to 2 years 5 months).

Secondary Outcomes

PFS Assessed by the Investigators (INV-PFS), According to RECIST v1.1

PFS was defined as the time from randomization to the first occurrence of PD, as determined by the investigator per RECIST v1.1, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. Data for participants who did not experience PD or death was censored at the last tumor assessment date. Data for participants with no post-baseline tumor assessments were censored at the randomization date. PFS was estimated using KM method.

Time frame: From randomization to the first occurrence of PD according to RECIST v1.1, or death from any cause, whichever occurred first (up to 2 years 5 months)

Investigator-assessed Objective Response Rate (ORR) (INV-ORR), According to RECIST v1.1

ORR was defined as the percentage of participants with an objective response i.e. a complete response (CR) or partial response (PR) at two consecutive tumor assessments at least 28 days apart, as determined by the investigator per RECIST v1.1. CR was defined as the disappearance of all target lesions, and any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR.

Time frame: Up to 2 years 5 months

IRF-assessed ORR (IRF-ORR) According to RECIST v1.1

ORR was defined as the percentage of participants with an objective response i.e. a CR or PR at two consecutive tumor assessments at least 28 days apart, as determined by the IRF per RECIST v1.1. CR was defined as the disappearance of all target lesions, and any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR.

Time frame: Up to 2 years 5 months

Investigator-assessed Duration of Response (DOR) (INV-DOR), According to RECIST v1.1

DOR was defined as the time from the first occurrence of an objective response (CR or PR) to PD or death, whichever occurred first, as determined by the investigator per RECIST v1.1. CR was defined as the disappearance of all target lesions, and any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. DOR was estimated using KM method.

Time frame: From the date of first occurrence of a documented objective response to PD or death from any cause, whichever occurred first (up to 2 years 5 months)

IRF-assessed DOR (IRF-DOR) According to RECIST v1.1

DOR was defined as the time from the first occurrence of an objective response (CR or PR) to PD or death, whichever occurred first, as determined by IRF per RECIST v1.1. CR was defined as the disappearance of all target lesions, and any pathological lymph nodes must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD at prior timepoints (including baseline). In addition to the relative increase of 20%, the SOD must also demonstrate an absolute increase of ≥ 5 mm. DOR was estimated using KM method.

Time frame: From the date of first occurrence of a documented objective response to PD or death from any cause, whichever occurred first (up to 2 years 5 months)

Number of Participants With Adverse Events (AEs)

An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Time frame: Up to approximately 50 months

Serum Concentration of Atezolizumab

Time frame: Predose on Day 1 of Cycles 1, 2, 3, 4, 8, 12 and 16; 30 minutes postdose on Cycle 1 Day 1 (1 cycle = 21 days); Treatment discontinuation visit (up to approximately 46 months)

Plasma Concentration of Cabozantinib

Time frame: Predose on Day 1 of Cycles 2, 3, and 4 (1 cycle = 21 days); Treatment discontinuation visit (up to approximately 48 months)

Percentage of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab

Participants who received atezolizumab were considered to be treatment-emergent ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA-positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the titer of the baseline sample (treatment-enhanced ADA response).

Time frame: Up to approximately 24 months

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

Overview

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Interventions

Eligibility

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Outcomes

Primary Outcomes

Secondary Outcomes