Safety and Pharmacology Study of Atezolizumab Alone and in Combination With Bacille Calmette-Guérin (BCG) in High-Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) Participants

Study Overview
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Brief Summary
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This Phase Ib/II study is designed to assess the safety, tolerability, pharmacokinetics, immunogenicity, patient reported outcomes (PROs), and preliminary anti-tumor activity of atezolizumab administered by intravenous (IV) infusion alone and in combination with intravesical BCG in high-risk NMIBC participants. The study will be conducted in following cohorts: Cohort 1A, Cohort 1B, Cohort 2, and Cohort 3. Atezolizumab will be administered at a fixed dose of 1200 milligrams (mg) every 3 weeks (q3w) for a maximum of 96 weeks. BCG will be administered to evaluate dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), or maximum administered dose (MAD). De-escalation will be allowed for up to three dose levels of BCG (full dose [50 mg], 66 percent [%] of a full dose, and 33% of a full dose [Cohort 1B only]). After the MTD or MAD is determined for Cohort 1B, this dose will be used for all subsequent participants enrolled into Cohorts 1B, 2, and 3, unless the MTD is determined to be 33% of a full BCG dose. If MTD is determined to be 33% of a full BCG dose, then, no participants will be enrolled into Cohorts 2 and 3 until an assessment of the safety and activity of the combination of atezolizumab plus 33% of a full BCG dose is completed.

Official Title
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A Phase Ib/II, Open-Label Study of the Safety and Pharmacology of Atezolizumab Administered With or Without Bacille Calmette-Guérin in Patients With High-Risk Non-Muscle-Invasive Bladder Cancer

Conditions
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Bladder Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Biological: Bacille Calmette-Guérin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed non-muscle-invasive transitional cell carcinoma (TCC) of the bladder with carcinoma in-situ (CIS) High-risk NMIBC defined by the following: BCG-unresponsive NMIBC: Persistence of high-grade CIS at 6 months following an adequate course of BCG; or Stage/grade progression at 3 months after induction BCG; or Recurrence of high-grade CIS after achieving a disease-free state (i.e., CR) following induction of an adequate course of BCG that occurs less than (<) 6 months after the last exposure to BCG BCG-relapsing NMIBC: Recurrence of high-grade CIS after achieving a disease-free state following induction of an adequate course of BCG that occurs greater than or equal to (>/=) 6 months after the last exposure to BCG Very high-risk (VHR) BCG-naïve NMIBC: VHR NMIBC, defined as having at least 1 of the following: Multiple and/or large (greater than [>] 3 centimeters [cm]) T1, (HG/G3) tumors; T1, (HG/G3) tumor with concurrent CIS; T1, G3 with CIS in prostatic urethra; Micropapillary variant of non-muscle invasive urothelial carcinoma For BCG-unresponsive and BCG-relapsing NMIBC, participants must have received an adequate course of BCG Resection of all pTa/pT1 papillary disease No prior radiation to bladder or pelvic region Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (</=) 2; Life expectancy >/=12 weeks Adequate hematologic and end-organ function Creatinine clearance >/=30 milliliters per minute (mL/min) (calculated using the Cockcroft-Gault formula) For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 5 months after the last dose of study drug. Women must refrain from donating eggs during this same period. For men receiving BCG: Agreement to remain abstinent (refrain from sexual intercourse) or use a condom Tumor tissue biopsy within 60 days prior to study entry or availability of an archival specimen obtained within 60 days of study screening Exclusion Criteria: Evidence of locally advanced, metastatic, muscle-invasive, and/or extravesical bladder cancer Any malignancy within 5 years prior to Cycle 1, Day 1 History of autoimmune disease, idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or active pneumonitis Signs or symptoms of infection within 2 weeks prior to the first dose of study treatment Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to the first dose of study treatment Treatment with any approved anti-cancer therapy within 3 weeks prior to the first dose of study treatment Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to the first dose of study treatment Pregnant or lactating women, or women intending to become pregnant during the study Prior allogeneic stem cell or solid organ transplantation Positive test for human immunodeficiency virus (HIV) Active hepatitis B or C and/or tuberculosis Severe infections within 28 days prior to the first dose of study treatment Significant cardiovascular disease Major surgical procedure other than for diagnosis within 4 weeks prior to the first dose of study treatment, or anticipation of need for a major surgical procedure during the course of the study Administration of a live/attenuated vaccine within 4 weeks prior to the first dose of study treatment, within 5 months following the administration of the last dose of study drug, or anticipation that such a live/attenuated vaccine will be required during the study History of prior significant toxicity or intolerance to BCG requiring discontinuation of treatment History of prior systemic BCG infection History of immunosuppression, or conditions associated with congenital or acquired immune deficiency Concurrent febrile illness, urinary tract infection, or gross hematuria Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies Treatment with systemic immunostimulatory agents within 6 weeks or five half-lives of the drug, whichever is shorter, prior to the first dose of study treatment Treatment with systemic immunosuppressive medications within 2 weeks prior to the first dose of study treatment, or anticipated requirement for systemic immunosuppressive medications during the trial

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1A: Atezolizumab (BCG-unresponsive NMIBC)<br>Participants will receive atezolizumab 1200 mg IV infusion q3w, for a maximum of 32 doses or 96 weeks of therapy, whichever comes first. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in respective arm.<br>* Other names: MPDL3280A;|
| Experimental: Cohort 1B: Atezolizumab + BCG (BCG-unresponsive NMIBC)<br>During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. Optional BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in respective arm.<br>* Other names: MPDL3280A;Biological: Bacille Calmette-Guérin<br>* For Cohort 1B, BCG will be administered (intravesically) at de-escalated doses. De-escalation will be allowed for up to three dose levels of BCG: full dose (50 mg), 66% of full dose, and 33% of full dose. After the MTD or MAD is determined for Cohort 1B, MTD/MAD will be used for all subsequent participants enrolled into Cohorts 1B, 2, and 3 (provided MAD or MTD is determined to be either full dose or 66% of a full BCG dose).<br>* Other names: OncoTICE®;|
| Experimental: Cohort 2: Atezolizumab + BCG (BCG-relapsing NMIBC)<br>During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. During BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in respective arm.<br>* Other names: MPDL3280A;Biological: Bacille Calmette-Guérin<br>* For Cohort 1B, BCG will be administered (intravesically) at de-escalated doses. De-escalation will be allowed for up to three dose levels of BCG: full dose (50 mg), 66% of full dose, and 33% of full dose. After the MTD or MAD is determined for Cohort 1B, MTD/MAD will be used for all subsequent participants enrolled into Cohorts 1B, 2, and 3 (provided MAD or MTD is determined to be either full dose or 66% of a full BCG dose).<br>* Other names: OncoTICE®;|
| Experimental: Cohort 3: Atezolizumab + BCG (BCG-naive NMIBC)<br>During BCG induction course (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of six doses. During BCG maintenance course 1 (12 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of four doses plus BCG at the assigned dose weekly for a total of three doses. During BCG maintenance courses 2-5 (each 24 weeks), participants will receive atezolizumab 1200 mg IV infusion q3w for a total of eight doses per course plus BCG at the assigned dose weekly for a total of three doses per course. | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in respective arm.<br>* Other names: MPDL3280A;Biological: Bacille Calmette-Guérin<br>* For Cohort 1B, BCG will be administered (intravesically) at de-escalated doses. De-escalation will be allowed for up to three dose levels of BCG: full dose (50 mg), 66% of full dose, and 33% of full dose. After the MTD or MAD is determined for Cohort 1B, MTD/MAD will be used for all subsequent participants enrolled into Cohorts 1B, 2, and 3 (provided MAD or MTD is determined to be either full dose or 66% of a full BCG dose).<br>* Other names: OncoTICE®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events | Percentage of participants with at least one adverse event during the study. | From Baseline up to end of study (up to approximately 4.3 years) | 
| Cohort 1B: Percentage of Participants With DLTs of BCG | Percentage of participants with dose-limiting toxicities (DLT) of BCG in Cohort 1B. | Days 1-21 | 
| Cohort 1B: MAD of BCG | Maximum administered dose (MAD) of BCG. | Days 1-21 | 
| Percentage of Participants With Complete Response (CR) as Assessed by the Investigator on the Basis of Cystoscopy and Urine Cytology at Month 6 | CR at 6 months after the start of study treatment as assessed by the investigator on the basis of cystoscopic assessment and urine cytology. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With CR as Assessed by the Investigator on the Basis of Cystoscopy and Urine Cytology at Month 3 | CR at the 3-month disease assessment, evaluated by both cystoscopy and cytology. | 3 months | 
| Duration of CR, as Assessed on the Basis of Cystoscopy and Urine Cytology | Duration of CR will be defined for participants with a CR as the time from the first occurrence of a documented complete response to recurrence of high-grade NMIBC or death from any cause. | From first occurence of a documented CR until the time of recurrence of NMIBC or death from any cause (up to approximately 4.3 years) | 
| Percentage of Participants With Recurrence-Free Survival (RFS), as Assessed on the Basis of Cystoscopy and Urine Cytology | RFS rate at 6, 12, and 18 months, defined as the proportion of patients who are alive and free of persistent/recurrent high-grade NMIBC. | 6, 12 and 18 months | 
| Bladder-Intact Disease-Free Survival (DFS), as Assessed on the Basis of Cystoscopy and Urine Cytology | Bladder-intact DFS was defined as the time from the first study treatment to earliest evidence of progression to muscle-invasive disease in the bladder, regional pelvic progression, distant metastasis, bladder cancer-related death, or cystectomy. | From first study treatment to earliest evidence of progression to muscle-invasive disease in the bladder, regional pelvic progression, distant metastasis, bladder cancer-related death, or cystectomy or death from any cause (up to approximately 4.3 years) | 
| Progression-Free Survival (PFS), as Assessed on the Basis of Cystoscopy and Urine Cytology | PFS, defined as the time from the first study treatment to the first occurrence of progression to muscle-invasive disease based on cystoscopy and urine cytology or death from any cause. | Time from first study treatment to the first occurrence of progression to muscle-invasive disease or death from any cause (up to approximately 4.3 years) | 
| Cystectomy-Free Survival (CFS), as Assessed on the Basis of Cystoscopy and Urine Cytology | Cystectomy-free survival, defined as from start of study treatment to bladder removal for any cause or death from any cause. | Time from first study treatment to cystectomy or death from any cause (up to approximately 4.3 years) | 
| Overall Survival |  | Time from first study treatment to death from any cause (up to approximately 4.3 years) | 
| Maximum Observed Serum Concentration of Atezolizumab (Cmax) | Maximum observed serum concentration of Atezolizumab (Cmax) | Cycle 1 Day 1 post-dose (Cycle length=21 days) | 
| Minimum Observed Serum Concentration of Atezolizumab (Cmin) | Minimum observed serum concentration of atezolizumab (Cmin) | Pre-dose (0 hr) on Day 1 of Cycles 2, 3, 4 and 8 (Cycle length=21 days) | 
| Percentage of Participants With Anti-Therapeutic Antibody (ADA) Response to Atezolizumab | Percentage of participants with anti-therapeutic antibody (ADA) response to atezolizumab. | Pre-dose (0 hr) on Day 1 of Cycles 1, 2, 3, 4, 8, 16, 24 (Cycle length=21 days), end of atezolizumab treatment (up to 96 weeks), 120 days after end of atezolizumab treatment (up to 113 weeks) |