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

NCT02792192 | Terminated Phase 1 Results DMC

• 1 other identifier: WO29635
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 8

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.

Conditions

Bladder Cancer

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (10)

• Percentage of Participants With CR as Assessed by the Investigator on the Basis of Cystoscopy and Urine Cytology at Month 3

  3 months

• 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)

• Percentage of Participants With Recurrence-Free Survival (RFS), as Assessed on the Basis of Cystoscopy and Urine Cytology

  6, 12 and 18 months

• 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)

• 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)

Study Arms (4)

Cohort 1A: Atezolizumab (BCG-unresponsive NMIBC)

EXPERIMENTAL

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

Cohort 1B: Atezolizumab + BCG (BCG-unresponsive NMIBC)

EXPERIMENTAL

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; Biological: Bacille Calmette-Guérin

Cohort 2: Atezolizumab + BCG (BCG-relapsing NMIBC)

EXPERIMENTAL

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; Biological: Bacille Calmette-Guérin

Cohort 3: Atezolizumab + BCG (BCG-naive NMIBC)

EXPERIMENTAL

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; Biological: Bacille Calmette-Guérin

Interventions

Atezolizumab DRUG

Atezolizumab will be administered as per the schedule specified in respective arm.

Also known as: MPDL3280A

Cohort 1A: Atezolizumab (BCG-unresponsive NMIBC); Cohort 1B: Atezolizumab + BCG (BCG-unresponsive NMIBC); Cohort 2: Atezolizumab + BCG (BCG-relapsing NMIBC); Cohort 3: Atezolizumab + BCG (BCG-naive NMIBC)

Bacille Calmette-Guérin BIOLOGICAL

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).

Also known as: OncoTICE®

Cohort 1B: Atezolizumab + BCG (BCG-unresponsive NMIBC); Cohort 2: Atezolizumab + BCG (BCG-relapsing NMIBC); Cohort 3: Atezolizumab + BCG (BCG-naive NMIBC)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (8)

Stanford Univ.

Stanford, California, 94305, United States

Location

University of Chicago Medical Center

Chicago, Illinois, 60637, United States

Location

Johns Hopkins Kimmel Cancer Center, Office of Research Administration

Baltimore, Maryland, 21205, United States

Location

The Montefiore Medical Center & The Albert Einstein College of Medicine; Department of Urology

The Bronx, New York, 10461, United States

Location

Duke University

Durham, North Carolina, 27705, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Oklahoma University Health Sciences Center

Oklahoma City, Oklahoma, 73104, United States

Location

VA Portland Healthcare System

Portland, Oregon, 97239, United States

Location

Related Publications (1)

• Inman BA, Hahn NM, Stratton K, Kopp R, Sankin A, Skinner E, Pohar K, Gartrell BA, Pham S, Rishipathak D, Mariathasan S, Davarpanah N, Carter C, Steinberg GD. A Phase 1b/2 Study of Atezolizumab with or Without Bacille Calmette-Guerin in Patients with High-risk Non-muscle-invasive Bladder Cancer. Eur Urol Oncol. 2023 Jun;6(3):313-320. doi: 10.1016/j.euo.2023.01.013. Epub 2023 Feb 15.

  PMID: 36803840 DERIVED

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

atezolizumab; BCG Vaccine

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Tuberculosis Vaccines; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures

Limitations and Caveats

Participants were enrolled only in Cohort 1 of this study. The Sponsor decided not to enroll participants in Cohorts 2 and 3 after the enrollment of 24 patients in Cohort 1 (BCG-unresponsive cohort), as the study had met its goals of providing preliminary safety and efficacy information for atezolizumab monotherapy alone and in combination with BCG in NMIBC.

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 2, 2016
• First Posted: June 7, 2016
• Study Start: June 13, 2016
• Primary Completion: September 29, 2020
• Study Completion: September 29, 2020
• Last Updated: October 28, 2021
• Results First Posted: October 28, 2021

Record last verified: 2021-09

Locations

US (8)