Study of Cabozantinib in Combination With Atezolizumab Versus Second NHT in Subjects With mCRPC

Study Overview
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Brief Summary
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This is a Phase 3, multi-center, randomized, open-label, controlled study designed to evaluate the safety and efficacy of cabozantinib given in combination with atezolizumab versus a second novel hormonal therapy (NHT) in men with metastatic castration-resistant prostate cancer (mCRPC) who have previously been treated with one, and only one, NHT for their prostate cancer disease.

Detailed Description
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The primary objective of this study is to evaluate the efficacy of cabozantinib (XL184) in combination with atezolizumab versus a second NHT (abiraterone or enzalutamide) in subjects with mCRPC who have previously been treated with one, and only one, NHT (e.g. abiraterone, apalutamide, darolutamide, or enzalutamide) to treat metastatic castration-sensitive prostate cancer (mCSPC), non-metastatic CRPC (M0 CRPC), or mCRPC, and who have measurable extrapelvic disease. The multiple primary efficacy endpoints comparing the experimental arm and control arm are Duration of Progression Free Survival (PFS) per RECIST 1.1 by Blinded Independent Radiology Committee (BIRC) and Duration of Overall Survival (OS). The secondary efficacy endpoint is Objective Response Rate (ORR) per RECIST 1.1 per BIRC.

Official Title
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A Phase 3, Randomized, Open-Label, Controlled Study of Cabozantinib (XL184) in Combination With Atezolizumab vs Second Novel Hormonal Therapy (NHT) in Subjects With Metastatic Castration-Resistant Prostate Cancer

Conditions
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Metastatic Prostate Cancer, Prostate Adenocarcinoma

Intervention / Treatment
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* Drug: Cabozantinib
* Drug: Atezolizumab
* Drug: Abiraterone Acetate
* Drug: Enzalutamide
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men with histologically or cytologically confirmed adenocarcinoma of the prostate Prior treatment with one, and only one, NHT (eg, abiraterone, apalutamide, darolutamide, or enzalutamide) for castration-sensitive locally advanced (T3 or T4) or mCSPC, M0 CRPC, or mCRPC Surgical or medical castration, with serum testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening Measurable (extrapelvic soft tissue) metastatic disease per Investigator assessment defined by at least one of the following: measurable visceral disease (eg, adrenal, kidney, liver, lung, pancreas, spleen) per RECIST 1.1; OR measurable extrapelvic adenopathy (ie, adenopathy above the aortic bifurcation) Progressive disease at study entry as defined by specific criteria for prostate specific antigen (PSA) progression OR soft tissue disease progression in the opinion of the Investigator (Note: subjects with bone disease progression alone are not eligible) Age ≥ 18 years old or meeting country definition of adult, whichever is older, on the day of consent ECOG performance status of 0 or 1 Recovery to baseline or ≤ Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy in the opinion of the Investigator Adequate organ and marrow function based upon specific laboratory assessments obtained within 21 days prior to randomization Understanding and ability to comply with protocol requirements Exclusion Criteria: Any prior nonhormonal therapy initiated for the treatment of mCRPC Receipt of abiraterone within 1 week; cyproterone within 10 days; or flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen-receptor inhibitors within 2 weeks before randomization Radiation therapy within 4 weeks (2 weeks for bone metastases) prior to randomization (subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible) Known brain metastases or cranial epidural disease unless adequately treated and clinically stable at least 4 weeks prior to randomization Symptomatic or impending spinal cord compression or cauda equina syndrome Concomitant anticoagulation with oral anticoagulants (some specific exceptions apply) Administration of a live, attenuated vaccine within 30 days prior to randomization Systematic treatment with, or any condition requiring, either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to randomization Uncontrolled, significant intercurrent or recent illness Major surgery within 4 weeks prior to randomization Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per ECG within 21 days before randomization Inability or unwillingness to swallow pills or receive IV administration Previously identified allergy or hypersensitivity to components of the study treatment formulations or history of severe infusion-related reactions to monoclonal antibodies Any other active malignancy at time of randomization or diagnosis of another malignancy within 2 years prior to randomization that requires active treatment (some exceptions apply such as locally curable cancers that have apparently been cured).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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
Interventional Model Description: Approximately 580 eligible subjects will be randomized in a 1:1 fashion to the experimental arm receiving cabozantinib and atezolizumab in combination (290) or to the control arm receiving a second NHT (290).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Arm<br>Subjects with mCRPC will receive cabozantinib 40mg oral, qd + atezolizumab 1200mg infusion, q3w | Drug: Cabozantinib<br>* Supplied as 20-mg tablets; administered orally daily at 40mg<br>* Other names: Cabometyx®;Drug: Atezolizumab<br>* Supplied as 1200 mg/20 mL vials; administered as an IV infusion once every 3 weeks (q3w)<br>* Other names: Tecentriq®;|
| Active Comparator: Control Arm<br>Subjects with mCRPC will receive active comparator of EITHER abiraterone 1000mg oral, qd + prednisone 5 mg oral, bid; OR enzalutamide 160mg oral, qd as designated by the Investigator prior to randomization | Drug: Abiraterone Acetate<br>* Supplied as 500 mg tablets; administered orally daily at 1000mg with prednisone 5 mg orally bid<br>* Other names: Zytiga;Drug: Enzalutamide<br>* Supplied as 40 mg capsules; administered orally daily at 160mg<br>* Other names: Xtandi;Drug: Prednisone<br>* Supplied as 5 mg tablets; administered orally bid at 5 mg with abiraterone 1000mg orally daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Progression Free Survival per Response Evaluable Criteria in Solid Tumors version 1.1 (RECIST 1.1) | Defined as time from randomization to the earlier of progressive disease (PD) per RECIST 1.1 as determined by the Blinded Independent Radiology Committee (BIRC) or death from any cause | Approximately 21 months after the first subject is randomized. | 
| Duration of Overall Survival (OS) | Defined as time from randomization to date of death from any cause | Approximately 37 months after the first subject is randomized | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR per RECIST 1.1 by BIRC | Approximately 37 months after the first subject is randomized | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer, castration-resistant prostate cancer