Clinical trial NCT02108652: A Study of Atezolizumab in Participants With Locally Advanced or Metastatic Urothelial Bladder Cancer (Cohort 2)
Official title: A Phase II, Multicenter, Single-Arm Study of Atezolizumab in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bladder Cancer
Keywords: anti-PD-L1
PD-L1
MPDL3280A
PD-1
bladder cancer
atezolizumab
Tecentriq
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2014-04-09
Enrollment: 310
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This Phase II, single-arm study is designed to evaluate the effect of atezolizumab treatment in participants with locally advanced or metastatic urothelial bladder cancer. Participants will be enrolled into 1 of 2 cohorts. Cohort 1 will consist of participants who are treatment-naïve and ineligible for cisplatin-containing chemotherapy. The results of Cohort 1 are reported separately (NCT02951767). Cohort 2 (reported here) will contain participants who have progressed during or following a prior platinum-based chemotherapy regimen. Participants in both cohorts will be given a 1200 milligrams (mg) intravenous (IV) dose of atezolizumab on Day 1 of 21-day cycles. Treatment of participants in Cohort 1 will continue until disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) or unmanageable toxicity. Treatment of participants in Cohort 2 will continue until loss of clinical benefit or unmanageable toxicity.


Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary bladder, urethra)
* Representative tumor specimens as specified by the protocol
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Life expectancy greater than or equal to (\>=) 12 weeks
* Measurable disease, as defined by RECIST v1.1
* Adequate hematologic and end organ function

Cohort 2-Specific Inclusion Criteria

* Disease progression during or following treatment with at least one platinum-containing regimen (e.g., gemcitabine and cisplatin \[GC\], methotrexate, vinblastine, doxorubicin, and cisplatin \[MVAC\], CarboGem, etc.) for inoperable locally advanced or metastatic urothelial carcinoma or disease recurrence.
* A regimen was defined as participants receiving at least two cycles of a platinum-containing regimen. Participants who had received one cycle of a platinum-containing regimen but discontinued due to Grade 4 hematologic toxicity or Grade 3 or 4 non-hematologic toxicity could also be eligible.
* Participants who received prior adjuvant/neoadjuvant chemotherapy and progressed within 12 months of treatment with a platinum-containing adjuvant/neoadjuvant regimen were considered as second-line participants.

Exclusion Criteria:

* Any approved anti-cancer therapy within 3 weeks prior to initiation of study treatment
* Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrollment
* Active or untreated central nervous system (CNS) metastases as determined by computed tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments
* Leptomeningeal disease
* Uncontrolled tumor-related pain
* Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
* Uncontrolled hypercalcemia (greater than \[\>\] 1.5 millimoles per liter \[mmol/L\] ionized calcium or Ca \> 12 milligrams per deciliter \[mg/dL\] or corrected serum calcium \> upper limits of normal \[ULN\]) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
* Malignancies other than urothelial bladder cancer within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome or incidental prostate cancer
* Pregnant and lactating women
* History of autoimmune disease
* History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
* Serum albumin less than (\<) 2.5 grams per deciliter (g/dL)
* Positive test for human immunodeficiency virus (HIV) and/or active hepatitis B or hepatitis C or tuberculosis
* Severe infections within 4 weeks prior to Cycle 1, Day 1
* Significant cardiovascular disease
* Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1
* Prior allogeneic stem cell or solid organ transplant
* Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1
* Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
* Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4), anti-programmed death-1 receptor (anti-PD-1), and anti-programmed death-ligand 1 (anti-PD-L1) therapeutic antibodies

Primary outcomes:
measure: Percentage of Participants With a Confirmed Objective Response of Complete Response (CR) or Partial Response (PR) as Assessed by the Independent Review Facility (IRF) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: Percentage of Participants With a Confirmed Objective Response of CR or PR as Assessed by the Investigator According Modified RECIST
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
Secondary outcomes:
measure: Duration of Response (DOR) as Assessed by the IRF According to RECIST v1.1
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: DOR as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: DOR as Assessed by the Investigator According to Modified RECIST
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: Percentage of Participants With Death or Disease Progression as Assessed by the IRF According to RECIST v1.1
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: Progression-Free Survival (PFS) as Assessed by the IRF According to RECIST v1.1
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: Percentage of Participants With Death or Disease Progression as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: PFS as Assessed by the Investigator According to RECIST v1.1
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: Percentage of Participants With Death or Disease Progression as Assessed by the Investigator According to Modified RECIST
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: PFS as Assessed by the Investigator According to Modified RECIST
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: Percentage of Participants With a Confirmed Objective Response of CR or PR as Assessed by the Investigator According RECIST v1.1
timeFrame: Baseline until confirmed disease progression or death, whichever occurred first (assessed at every 9 weeks for the first 12 months, thereafter every 12 weeks until data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: Percentage of Participants Who Died
timeFrame: Baseline until death (data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: Overall Survival (OS)
timeFrame: Baseline until death (data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
measure: Percentage of Participants Alive at 1-year
timeFrame: 1-year
measure: Maximum Serum Concentration (Cmax) of Atezolizumab
timeFrame: Pre-dose (0 hours) and 30 minutes post-dose on Day 1 of Cycle 1 (Cycle length = 21 days)
measure: Minimum Serum Concentration (Cmin) of Atezolizumab
timeFrame: Pre-dose (0 hours) on Day 1 of Cycles 1, 2, 3, 4, 8 (Cycle length = 21 days)
measure: Percentage of Participants Positive for Anti-therapeutic Antibodies (ATA) to Atezolizumab
timeFrame: Day 1 of all cycles (Cycle length = 21 days) and at treatment discontinuation (data cutoff date 04 July 2016, up to maximum length of follow-up of 24.48 months)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama At Birmingham
state: Alabama
city: Scottsdale
country: United States
facility: Pinnacle Oncology Hematology
state: Arizona
city: Tucson
country: United States
facility: Arizona Oncology - HOPE Wilmot
state: Arizona
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute - W LA Office
state: California
city: Los Angeles
country: United States
facility: USC Norris Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF
state: California
city: San Marcos
country: United States
facility: Kaiser Permanente - San Marcos
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente; Oncology Clinical Trials
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Center - Aurora
state: Colorado
city: Aurora
country: United States
facility: University Of Colorado
state: Colorado
city: Farmington
country: United States
facility: University of Connecticut Health Center
state: Connecticut
city: New Haven
country: United States
facility: Yale Cancer Center ; Medical Oncology
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center Lombardi Cancer Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Piedmont Cancer Institute, PC
state: Georgia
city: Chicago
country: United States
facility: University of Chicago; Hematology/Oncology
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Goshen
country: United States
facility: Indiana University Health; Goshen Center for Cancer Care
state: Indiana
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Boston
country: United States
facility: Massachusetts General Hospital;Oncology
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Inst. ; Dept. of Medical Oncology
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Medicine
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: Minnesota Oncology Minneapolis
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Omaha
country: United States
facility: Urology Cancer Center & GU Research Network
state: Nebraska
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Albany
country: United States
facility: New York Oncology Hematology, P.C.
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine - Tisch Cancer Institute
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve Univ; Hem/Onc
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Eugene
country: United States
facility: Willamette Valley Cancer Ctr - 520 Country Club
state: Oregon
city: Philadelphia
country: United States
facility: Kimmel Cancer Center Thomas Jefferson University
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Cancer Center - Tennessee Oncology, Pllc
state: Tennessee
city: Fort Worth
country: United States
facility: Ctr for Cancer and Blood Disorders
state: Texas
city: Houston
country: United States
facility: Texas Oncology - Houston (Gessner)
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates - Lake Wright Cancer Center
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Kelowna
country: Canada
facility: Bcca - Cancer Center Southern Interior
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA-Vancouver Cancer Centre
state: British Columbia
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa; Oncology
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital Cancer Centre; Oncology
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network; Princess Margaret Hospital; Medical Oncology Dept
state: Ontario
city: Montreal
country: Canada
facility: McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology
state: Quebec
city: Paris
country: France
facility: APHP - Hospital Saint Louis
city: Suresnes
country: France
facility: Hopital Foch; Oncologie
city: Villejuif
country: France
facility: Institut Gustave Roussy; Oncologie Medicale
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin; CC 8: Chirurgische Medizin; Klinik für Urologie
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf; Urologische Klinik
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg; Chirurgische Klinik; Abteilung Urologie
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf Onkologisches Zentrum Medizinische Klinik II
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München; Urologische Klinik und Poliklinik
city: Milano
country: Italy
facility: Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 2
state: Lombardia
city: Arezzo
country: Italy
facility: Azienda USL8 Arezzo-Presidio Ospedaliero 1 San Donato;U.O.C. Oncologia
state: Toscana
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute - Antoni Van Leeuwenhoekziekenhuis
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra; Servicio de Oncologia
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Univ Vall d'Hebron; Servicio de Oncologia
city: Barcelona
country: Spain
facility: Institut Catala d Oncologia Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre; Servicio de Oncologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio; Servicio de Oncologia
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham The Cancer Centre, Queen Elizabeth Hospital
city: London
country: United Kingdom
facility: Barts and The London
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital; Dept of Medical Oncology
city: Wirral
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Holm JS, Funt SA, Borch A, Munk KK, Bjerregaard AM, Reading JL, Maher C, Regazzi A, Wong P, Al-Ahmadie H, Iyer G, Tamhane T, Bentzen AK, Herschend NO, De Wolf S, Snyder A, Merghoub T, Wolchok JD, Nielsen M, Rosenberg JE, Bajorin DF, Hadrup SR. Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma. Nat Commun. 2022 Apr 11;13(1):1935. doi: 10.1038/s41467-022-29342-0.
citation: Shemesh CS, Chan P, Legrand FA, Shames DS, Das Thakur M, Shi J, Bailey L, Vadhavkar S, He X, Zhang W, Bruno R. Pan-cancer population pharmacokinetics and exposure-safety and -efficacy analyses of atezolizumab in patients with high tumor mutational burden. Pharmacol Res Perspect. 2020 Dec;8(6):e00685. doi: 10.1002/prp2.685.
citation: Teo MY, Seier K, Ostrovnaya I, Regazzi AM, Kania BE, Moran MM, Cipolla CK, Bluth MJ, Chaim J, Al-Ahmadie H, Snyder A, Carlo MI, Solit DB, Berger MF, Funt S, Wolchok JD, Iyer G, Bajorin DF, Callahan MK, Rosenberg JE. Alterations in DNA Damage Response and Repair Genes as Potential Marker of Clinical Benefit From PD-1/PD-L1 Blockade in Advanced Urothelial Cancers. J Clin Oncol. 2018 Jun 10;36(17):1685-1694. doi: 10.1200/JCO.2017.75.7740. Epub 2018 Feb 28.
citation: Perez-Gracia JL, Loriot Y, Rosenberg JE, Powles T, Necchi A, Hussain SA, Morales-Barrera R, Retz MM, Niegisch G, Duran I, Theodore C, Grande E, Shen X, Wang J, Nelson B, Derleth CL, van der Heijden MS. Atezolizumab in Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: Outcomes by Prior Number of Regimens. Eur Urol. 2018 Mar;73(3):462-468. doi: 10.1016/j.eururo.2017.11.023. Epub 2017 Dec 20.
citation: Necchi A, Joseph RW, Loriot Y, Hoffman-Censits J, Perez-Gracia JL, Petrylak DP, Derleth CL, Tayama D, Zhu Q, Ding B, Kaiser C, Rosenberg JE. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: post-progression outcomes from the phase II IMvigor210 study. Ann Oncol. 2017 Dec 1;28(12):3044-3050. doi: 10.1093/annonc/mdx518.
citation: Snyder A, Nathanson T, Funt SA, Ahuja A, Buros Novik J, Hellmann MD, Chang E, Aksoy BA, Al-Ahmadie H, Yusko E, Vignali M, Benzeno S, Boyd M, Moran M, Iyer G, Robins HS, Mardis ER, Merghoub T, Hammerbacher J, Rosenberg JE, Bajorin DF. Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis. PLoS Med. 2017 May 26;14(5):e1002309. doi: 10.1371/journal.pmed.1002309. eCollection 2017 May.
citation: Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, Loriot Y, Necchi A, Hoffman-Censits J, Perez-Gracia JL, Dawson NA, van der Heijden MS, Dreicer R, Srinivas S, Retz MM, Joseph RW, Drakaki A, Vaishampayan UN, Sridhar SS, Quinn DI, Duran I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thastrom A, Abidoye OO, Fine GD, Bajorin DF; IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017 Jan 7;389(10064):67-76. doi: 10.1016/S0140-6736(16)32455-2. Epub 2016 Dec 8.
citation: Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016 May 7;387(10031):1909-20. doi: 10.1016/S0140-6736(16)00561-4. Epub 2016 Mar 4.