A Study of Atezolizumab Compared With Chemotherapy in Participants With Locally Advanced or Metastatic Urothelial Bladder Cancer [IMvigor211]

• ClinicalTrials.gov Identifier: NCT02302807
• Recruitment Status: Completed
• First Posted: November 27, 2014
• Results First Posted: April 11, 2018
• Last Update Posted: August 1, 2019
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: November 25, 2014
• First Posted Date: November 27, 2014
• Results First Submitted Date: March 13, 2018
• Results First Posted Date: April 11, 2018
• Last Update Posted Date: August 1, 2019
• Actual Study Start Date: January 13, 2015
• Actual Primary Completion Date: March 13, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 13, 2018)

Overall Survival (OS) [ Time Frame: Between randomization and death due to any cause, up to approximately 25 months after first participant enrolled ]

OS was defined as time from randomization to death from any cause.

• Original Primary Outcome Measures (submitted: November 26, 2014): Overall survival [ Time Frame: Between randomization and death due to any cause, up to approximately 23 months after first patient enrolled ]

Current Secondary Outcome Measures (submitted: July 5, 2019)

• Progression-free Survival (PFS) as Determined by the Investigator With Use of RECIST v1.1 [ Time Frame: Up to approximately 25 months after first participant enrolled ]
  PFS was defined as the time between the date of randomization and the date of first documented progression of disease (PD) or death, whichever occurred first. PD was determined on the basis of investigator assessment with use of RECIST v1.1. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters had to demonstrate an absolute increase of >/= 5 millimeters (mm).
• Unconfirmed Duration of Response (DOR) as Determined by the Investigator With Use of RECIST v1.1 [ Time Frame: Up to approximately 25 months after first participant enrolled ]
  DOR was defined as the time from first occurrence of a CR or PR, whichever came first, to first documented PD or death, whichever occurred first. Disease progression was determined on the basis of investigator assessment with use of RECIST v1.1. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/= 5 mm.
• Percentage of Participants With Adverse Events (AEs) [ Time Frame: Up to approximately 46 months after first participant enrolled ]
  An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
• Percentage of Participants With Post-Baseline Anti-therapeutic Antibodies (ATA) to Atezolizumab [ Time Frame: Predose (0 hours) on Day 1 of Cycles 1, 2, 3, 4 and every 8 cycles thereafter; at treatment discontinuation (up to 25 months); at 120 days after last dose of atezolizumab (up to 25 months; each cycle is 21 days) ]
  Participants were considered post-baseline ATA positive if they had post-baseline ATAs to Atezolizumab that were treatment-induced or treatment-enhanced. Participants had treatment-induced ATAs if they had a baseline-negative ATA result and developed ATAs at any time after initial drug administration. Participants had treatment-enhanced ATAs if they had a baseline-positive ATA result that showed an enhanced signal that was >/= 0.60 titer units at any time after initial drug initiation.
• Minimum Observed Serum Atezolizumab Concentration (Cmin) [ Time Frame: Predose (0 hours) on Day 1 of Cycles 1, 2, 3, 4 and every 8 cycles thereafter; at treatment discontinuation (up to 25 months); at 120 days after last dose of atezolizumab (up to 25 months; each cycle is 21 days) ]
  Cmin was measured for all participants that received at least one dose of Atezolizumab.
• Percentage of Participants With Unconfirmed Objective Response Rate (ORR) as Determined by the Investigator With Use of Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) [ Time Frame: Up to approximately 25 months after first participant enrolled ]
  ORR was defined as the percentage of participants, who had an objective response. Objective response was defined as either a complete response (CR) or partial response (PR) as determined by the investigator with use of Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). Objective response in this study did not need to be a confirmed response. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. ORR=CR+PR
• Maximum Observed Serum Atezolizumab Concentration (Cmax) [ Time Frame: 30 minutes post dose on Day 1 of Cycles 1 ]
  Cmax was measured for all participants that received at least one dose of Atezolizumab.
• Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Global Health Status Scale [ Time Frame: Cycle 1 Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, and at 30 days after the last treatment dose (Up to approximately 25 months; each cycle is 21 days) ]
  The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS.
• Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Physical Functioning Scale [ Time Frame: Cycle 1 Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, and at 30 days after the last treatment dose (Up to approximately 25 months; each cycle is 21 days) ]
  The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS.
• Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) Score: Fatigue Symptom Scale [ Time Frame: Cycle 1 Day 1 (prior to any health care interaction), on Day 1 of each subsequent cycle, and at 30 days after the last treatment dose (Up to approximately 25 months; each cycle is 21 days) ]
  The EORTC QLQ-C30 includes five functional scales (physical, role, cognitive, emotional, social); a global health status (GHS)/quality of life (QoL) scale; and items measuring fatigue, pain, nausea and vomiting, dyspnea, appetite loss, sleep disturbance, constipation, diarrhea, and financial difficulties. The score range for each scale and single-item measure is 0 to 100, where higher scores indicate a higher response level (i.e., better functioning, better QoL, worse symptoms). Key scales included physical functioning, and fatigue, and GHS.

Original Secondary Outcome Measures (submitted: November 26, 2014)

• Objective response rate (ORR) [ Time Frame: Up to approximately 23 months after first patient enrolled ]
• Progression-free survival (PFS) [ Time Frame: Up to approximately 23 months after first patient enrolled ]
• Duration of response (DOR) [ Time Frame: Up to approximately 23 months after first patient enrolled ]
• Incidence of adverse events (AEs) [ Time Frame: Up to approximately 23 months after first patient enrolled ]
• Incidence of anti-therapeutic antibodies to MPDL3280A [ Time Frame: Up to approximately 23 months after first patient enrolled ]
• Maximum serum concentration (Cmax) of MPDL3280A [ Time Frame: Up to approximately 23 months after first patient enrolled ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Atezolizumab Compared With Chemotherapy in Participants With Locally Advanced or Metastatic Urothelial Bladder Cancer [IMvigor211]
• Official Title: A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) Compared With Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer After Failure With Platinum-Containing Chemotherapy
• Brief Summary: This is a Phase III, global, multicenter, open-label, two-arm, randomized, controlled study designed to evaluate the efficacy and safety of atezolizumab compared with chemotherapy in participants with locally advanced or metastatic urothelial bladder cancer (UBC) who have progressed during or following a platinum-containing regimen. The anticipated time on study treatment is based on continued clinical benefit, i.e., until disease progression or unacceptable toxicity. The target sample size is 931 participants.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Bladder Cancer

Intervention

• Drug: Atezolizumab (MPDL3280A) [TECENTRIQ], an engineered anti-PDL1 antibody
  Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.
  Other Name: Tecentriq
• Drug: Docetaxel
  Docetaxel 75 mg/m^2 will be administered intravenously on Day 1 of each 21-day cycle.
• Drug: Paclitaxel
  Paclitaxel 175 mg/m^2 will be administered intravenously on Day 1 of each 21-day cycle.
• Drug: Vinflunine
  Vinflunine 320 mg/m^2 will be administered intravenously on Day 1 of each 21-day cycle.

Study Arms

• Experimental: Arm A: Atezolizumab
  Atezolizumab will be administered intravenously at a fixed dose of 1200 milligrams (mg) on Day 1 of each 21-day cycle. Participants will receive atezolizumab as long as they continue to experience clinical benefit in the opinion of the investigator until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator.
  Intervention: Drug: Atezolizumab (MPDL3280A) [TECENTRIQ], an engineered anti-PDL1 antibody
• Active Comparator: Arm B: Chemotherapy (Vinflunine, Paclitaxel, or Docetaxel)
  Participants randomized to the chemotherapy arm will receive vinflunine, paclitaxel, or docetaxel per the investigator's choice. Vinflunine 320 milligrams per square meter (mg/m^2), paclitaxel 175 mg/m^2, or docetaxel 75 mg/m^2 will be administered intravenously on Day 1 of each 21-day cycle until disease progression per standard RECIST v1.1 or unacceptable toxicity.
  Interventions:

  • Drug: Docetaxel
  • Drug: Paclitaxel
  • Drug: Vinflunine

Publications *

• van der Heijden MS, Loriot Y, Duran I, Ravaud A, Retz M, Vogelzang NJ, Nelson B, Wang J, Shen X, Powles T. Atezolizumab Versus Chemotherapy in Patients with Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: A Long-term Overall Survival and Safety Update from the Phase 3 IMvigor211 Clinical Trial. Eur Urol. 2021 Jul;80(1):7-11. doi: 10.1016/j.eururo.2021.03.024. Epub 2021 Apr 23.
• 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.
• Morrissey KM, Marchand M, Patel H, Zhang R, Wu B, Phyllis Chan H, Mecke A, Girish S, Jin JY, Winter HR, Bruno R. Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting. Cancer Chemother Pharmacol. 2019 Dec;84(6):1257-1267. doi: 10.1007/s00280-019-03954-8. Epub 2019 Sep 21.
• Rassy EE, Bakouny Z, Aoun F, Haddad FG, Sleilaty G, Assi T, Kattan J. A network meta-analysis of the PD(L)-1 inhibitors in the salvage treatment of urothelial bladder cancer. Immunotherapy. 2018 Jun;10(8):657-663. doi: 10.2217/imt-2017-0190. Epub 2018 Mar 22.
• Powles T, Duran I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Flechon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018 Feb 24;391(10122):748-757. doi: 10.1016/S0140-6736(17)33297-X. Epub 2017 Dec 18. Erratum In: Lancet. 2018 Oct 20;392(10156):1402.
• 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. Erratum In: Lancet. 2017 Aug 26;390(10097):848.
• Kim YS, Lee SI, Park SH, Park S, Hwang IG, Lee SC, Sun JM, Lee J, Lim HY. A Phase II Study of Weekly Docetaxel as Second-Line Chemotherapy in Patients With Metastatic Urothelial Carcinoma. Clin Genitourin Cancer. 2016 Feb;14(1):76-81. doi: 10.1016/j.clgc.2015.09.008. Epub 2015 Sep 25.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 11, 2017): 931
• Original Estimated Enrollment (submitted: November 26, 2014): 767
• Actual Study Completion Date: November 8, 2018
• Actual Primary Completion Date: March 13, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically documented locally advanced or metastatic UBC (including renal pelvis, ureters, urinary bladder, and urethra).
• Representative tumor specimens as specified by the protocol
• Disease progression during or following treatment with at least one platinum-containing regimen for inoperable, locally advanced or metastatic UBC or disease recurrence
• 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
• For women of childbearing potential, agreement to 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 atezolizumab, 3 months after the last dose of vinflunine and 6 months from the last dose of paclitaxel or docetaxel.
• For men, agreement to 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 3 months after the last dose of vinflunine and 6 months from the last dose of paclitaxel or docetaxel, and agreement to refrain from donating sperm

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
• Malignancies other than UBC within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome, or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer
• Pregnant and lactating women
• Significant cardiovascular disease
• Severe infections within 4 weeks prior to randomization
• Major surgical procedure other than for diagnosis within 4 weeks prior to randomization
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins; known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
• History of autoimmune disease
• Prior allogeneic stem cell or solid organ transplant
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• Positive test for human immunodeficiency virus (HIV) and/or active hepatitis B or hepatitis C or tuberculosis
• Administration of a live, attenuated vaccine within 4 weeks prior to randomization
• Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), anti-programmed death-1 (anti-PD-1) or anti-programmed death-ligand 1 (anti-PD-L1) therapeutic antibodies

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, Italy, Japan, Korea, Republic of, Netherlands, Norway, Poland, Portugal, Romania, Russian Federation, Serbia, Slovenia, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02302807
• Other Study ID Numbers: GO29294; 2014-003231-19 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: July 2019