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

Phase 1

Terminated

Conditions: Bladder Cancer

Interventions: Drug: Atezolizumab
Biological: Bacille Calmette-Guérin

Registration Number: NCT02792192

Lead Sponsor: Hoffmann-La Roche

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 24

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 1B: Atezolizumab + BCG (BCG-unresponsive NMIBC)	Bacille Calmette-Guérin	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.
Cohort 2: Atezolizumab + BCG (BCG-relapsing NMIBC)	Bacille Calmette-Guérin	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.
Cohort 3: Atezolizumab + BCG (BCG-naive NMIBC)	Bacille Calmette-Guérin	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.
Cohort 1A: Atezolizumab (BCG-unresponsive NMIBC)	Atezolizumab	Participants will receive atezolizumab 1200 mg IV infusion q3w, for a maximum of 32 doses or 96 weeks of therapy, whichever comes first.
Cohort 1B: Atezolizumab + BCG (BCG-unresponsive NMIBC)	Atezolizumab	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.
Cohort 2: Atezolizumab + BCG (BCG-relapsing NMIBC)	Atezolizumab	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.
Cohort 3: Atezolizumab + BCG (BCG-naive NMIBC)	Atezolizumab	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.

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Cystectomy-Free Survival (CFS), as Assessed on the Basis of Cystoscopy and Urine Cytology	Time from first study treatment to cystectomy or death from any cause (up to approximately 4.3 years)	Cystectomy-free survival, defined as from start of study treatment to bladder removal for any cause or death from any cause.
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)	Cycle 1 Day 1 post-dose (Cycle length=21 days)	Maximum observed serum concentration of Atezolizumab (Cmax)
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)	Minimum observed serum concentration of atezolizumab (Cmin)
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)	Percentage of participants with anti-therapeutic antibody (ADA) response to atezolizumab.
Percentage of Participants With CR as Assessed by the Investigator on the Basis of Cystoscopy and Urine Cytology at Month 3	3 months	CR at the 3-month disease assessment, evaluated by both cystoscopy and cytology.
Duration of CR, as Assessed on the Basis of Cystoscopy and Urine Cytology	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)	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.
Percentage of Participants With Recurrence-Free Survival (RFS), as Assessed on the Basis of Cystoscopy and Urine Cytology	6, 12 and 18 months	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.
Bladder-Intact Disease-Free Survival (DFS), as Assessed on the Basis of Cystoscopy and Urine Cytology	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)	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.
Progression-Free Survival (PFS), as Assessed on the Basis of Cystoscopy and Urine Cytology	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)	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.

Trial Locations

Locations (8): Duke University
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Durham, North Carolina, United States
VA Portland Healthcare System
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Portland, Oregon, United States
University of Chicago Medical Center
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Chicago, Illinois, United States
The Montefiore Medical Center & The Albert Einstein College of Medicine; Department of Urology
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Bronx, New York, United States
Ohio State University
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Columbus, Ohio, United States
Stanford Univ.
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Stanford, California, United States
Johns Hopkins Kimmel Cancer Center, Office of Research Administration
🇺🇸
Baltimore, Maryland, United States
Oklahoma University Health Sciences Center
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Oklahoma City, Oklahoma, United States