Efficacy of Atezolizumab Concurrent With Radiotherapy in Patients With Muscle-invasive Bladder cáncer

Efficacy of Atezolizumab Concurrent With Radiotherapy in Patients With Muscle-invasive Bladder cáncer (Study ATEZOBLADDERPRESERVE)

Open, multicentre, phase II trial of atezolizumab with concurrent normofractionated radiotherapy in patients with localized muscle-invasive bladder cancer treated with a selective multimodality bladder conservative approach.

Study Overview

• Status: Active, not recruiting
• Conditions: Bladder Cancer
• Intervention / Treatment: Drug: Atezolizumab Injection [Tecentriq]; Radiation: External Beam Radiation Therapy (EBRT)

Detailed Description

STUDY DESIGN:

Open, multicentre, phase II trial of atezolizumab with concurrent normofractionated radiotherapy in patients with histologically confirmed diagnosis of muscle-invasive urothelial carcinoma of the bladder.

The bladder preserving therapy include combined modality therapy with:

STUDY TREATMENTS:

Investigational product (atezolizumab/Tecentriq ®):

• Route of administration: intravenous infusion.
• Duration of treatment: 16 weeks.
• Dosage: 1.200 mg intravenous every 3 weeks for a total of 6 doses. Atezolizumab is supplied as atezolizumab 1200 mg/20 mL vials (60 mg/mL) solution for intravenous infusion. After dilution, one mL of solution should contain approximately 4.4 mg of atezolizumab (1,200 mg/270 mL).

External Beam Radiation Therapy (EBRT): radiation

• Duration of treatment: 6 weeks
• Dosage: 60 Gy of radiotherapy in 30 fractions overs 6 weeks at 2Gy/day

STUDY POPULATION:

Adult patients (aged ≥18 years) with histologically confirmed diagnosis of muscle-invasive urothelial carcinoma of the bladder, in clinical stages T2-T4a who are not candidates for radical cystectomy by medical reasons, refusal or patient´s choice.

A total of 39 patients are estimated to be included in the study.

OBJECTIVES:

Primary objective:

The primary objective of the study is to determine the efficacy of atezolizumab concurrent with radiotherapy in terms of pathological complete response defined as a response of grade 5 according to Miller and Payne criteria in patients with muscle-invasive bladder cancer treated with bladder preservation intent.

Secondary objectives:

• To evaluate overall survival (OS).
• To evaluate disease specific survival (DSS).
• To evaluate disease free survival (DFS).
• To evaluate bladder intact disease-free survival (BIDFS).
• To calculate the number of patients with muscle invasive and non-muscle invasive local failure (LF).
• To determine the rate of distance metastases defined as the percentage of patients who develop metastases.
• To determine to the rate of patients with bladder preserved.
• To determine to the rate of immediate or late salvage cystectomy.
• The safety profile and tolerability of the combination of atezolizumab with concurrent radiotherapy.

Exploratory objectives:

• To determine the predictive role of the expression of PD-1 / PD-L1 and CD8 in terms of pCR, OS and DFS in bladder cancer patients treated with atezolizumab plus radiotherapy.
• The correlation between the levels of IFN-γ, interleukin 6 (IL-6), interleukin 18 (IL-18), or ITAC (also called CXCL11 or IP-9) and the efficacy parameters (pCR, OS and DFS) of the treatment with atezolizumab plus radiotherapy.

STUDY VISITS AND PROCEDURES:

The study includes the following visits:

• Screening: within the 28 days prior to starting the study treatment.
• Baseline visit: the first day of cycle 1
• Visits over the treatment period (16 weeks ± 7 days): from administration of the first dose of the study treatment to the administration of the last dose of atezolizumab or withdrawal from the treatment. Treatment will consist of the administration of atezolizumab at 1,200 mg intravenous every 3 weeks for 6 cycles
• Post-treatment follow-up: includes the biopsy and safety visit 1-2 months after the last dose of atezolizumab and a subsequent 5 years follow-up period after.
• End of study visit/ Early termination: In patients who end the study follow-up or prematurely withdraw from the study

• Study Type: Interventional
• Enrollment (Anticipated): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Granada, Spain, 18016
    • Hospital Clinico Universitario San Cecilio
  • Lugo, Spain, 27003
    • Hospital Universitario Lucus Augusti
  • Madrid, Spain, 28006
    • Hospital Universitario La Princesa
  • Madrid, Spain, 28050
    • Hospital HM Sanchinarro
  • Orense, Spain, 32005
    • Complejo Hospitalario Universitario Ourense
  • Oviedo, Spain, 33011
    • Hospital Universitario Central de Asturias
  • Valencia, Spain, 6015
    • Hospital Arnau de Vilanova
  • Barcelona
    • Manresa, Barcelona, Spain, 08243
      • Althaia Xarxa Assintencial
    • Sabadell, Barcelona, Spain, 08208
      • Consorci Corporacio Sanitaria Parc Tauli
  • Tarragona
    • Reus, Tarragona, Spain, 43204
      • Hospital Universitario Sant Joan de Reus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Patients must be 18 years of age or older.
2. Patients have histologically-confirmed diagnosis of muscle-invasive urothelial carcinoma of the bladder, in clinical stages T2-4a N0 M0, who are not candidates for radical cystectomy by medical reasons, refusal or patient's choice.
3. Patients who refuse treatment with cisplatin-based chemotherapy or in whom treatment with cisplatin-based therapy is not appropriate.
4. Patients must have ECOG performance status 0 to 2.
5. Patients must have adequate bone marrow function as defined by absolute neutrophil count >1.500/mm3; platelets >100.000/mm3 and HB ≥ 9g/dl.
6. Patients must have adequate renal and liver function as defined by calculated creatinine clearance >15ml/min.
7. Total bilirubin, SGOT (AST) and/or SGPT (ALT) < 2,5 times the upper limit of normal.
8. International Normalized Ration (INR) or Prothrombin Time (PT): ≤1.5 X ULN unless participant is receiving anticoagulant therapy (as long as PT or PTT is within therapeutic range of intended use of anticoagulants).
9. Activated Partial Thromboplastin Time (aPTT): ≤1.5 X ULN unless participant is receiving anticoagulant therapy (as long as PT or PTT is within therapeutic range of intended use of anticoagulants).
10. Female participant of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to registering the patient. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
11. Female participants of childbearing potential should be willing to use two methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 5 months after the last dose of study medication. Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
12. Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy (1).
13. A paraffin-embedded tumour sample must be available for the associate molecular study.

Exclusion criteria:

1. Previous treatment with radiotherapy to the bladder, systemic chemotherapy or immune checkpoint inhibitors. Prior intravesical BCG treatment for non-muscle invasive bladder cancer is allowed.
2. Presence of regional lymph node or metastatic extension of the disease.
3. Concurrent treatment with other experimental drugs (within 30 days prior to study entry) or other anti-cancer therapy.
4. History of prior malignancies within the preceding 5 years other than previously treated basal cell carcinoma of the skin, non-muscle invasive bladder cancer, incidental prostate carcinoma Stage T1a well differentiated prostatic carcinoma in men (Gleason = 3+3, PSA <5) and carcinoma in situ of the cervix.
5. Evidence of tumour-related moderate/severe hydronephrosis unless stented or with nephrostomy to preserve renal function.
6. Extensive or multifocal bladder carcinoma in situ (CIS) precluding curative chemoradiotherapy.
7. Bulky T3/T4a tumours unsuitable for curative treatment (i.e. > 5 cm in any dimension). Tumours measures must be done post-TUR via CT scan.
8. Patients with serious uncontrolled infection.
9. Has a known history of active BT (Bacillus Tuberculosis).
10. Has known history of, or any evidence of active, non-infectious pneumonitis.
11. Autoimmune diseases other than vitiligo, type I diabetes mellitus, residual hypothyroidism requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
12. Positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic acid antibody (HCV-Ab) indicating acute or chronic infection.
13. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
14. Subjects with a condition requiring systemic treatment with either corticosteroids (equivalent to > 10 mg/day prednisone) or other immune-suppressive medications within 14 days of study drug administration.
15. Women of child-bearing potential unwilling to be abstinent or use effective methods of birth control.
16. General medical or psychological conditions that would preclude appropriate informed consent or compliance with the protocol.

(1) Acceptable methods of effective contraception:

• Complete sexual abstinence for 14 days before the start of study treatment to 5 months after completion of the investigational treatment.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), or tubal ligation at least six weeks before taking study treatment.
• Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
• Intrauterine device or system with a documented failure less than 1%.
• Double barrier method with spermicide.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental arm; Atezolizumab 1200 mg intravenous infusion every 3 weeks for a total of 6 doses combined with External Beam Radiation Therapy (EBRT) (dosage: 60 Gy in 30 fractions overs 6 weeks at 2Gy/day)	Drug: Atezolizumab Injection [Tecentriq]; intravenous infusion of 1.200 mg of Atezolizumab administered intravenously every 3 weeks for a total of 6 doses; Radiation: External Beam Radiation Therapy (EBRT); 60 Gy of radiotherapy in 30 fractions overs 6 weeks at 2 Gy/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response	Response of grade 5 according to Miller and Payne criteria	After the end of the treatment (16 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Time from the date of the beginning of protocol therapy to the date of death due to any cause	through study completion, up to 5 years
Disease specific survival	Time from start of treatment to the date of having evidence of distant metastases, nodal recurrence or recurrence within the radiotherapy field that could be salvaged in a curative fashion, what happens first	through study completion, up to 5 years
Disease free survival	Time from the date of start of protocol therapy to the date of recurrence of muscle invasive or non-invasive bladder carcinoma or metastases, what happens first	through study completion, up to 5 years
Bladder-intact disease-free survival	Time from the date of initiation of protocol therapy until the development of MIBC recurrence, regional pelvic recurrence, distant metastases, bladder cancer-related death or cystectomy, what happens first	through study completion, up to 5 years
Muscle invasive and non-muscle invasive local failure	defined as patients that do not achieve a pCR defined as a response of grade 5 according to Miller and Payne criteria and documented tumour recurrence after pCR	through study completion, up to 5 years
Rate of distant metastases	Percentage of patients who develop distant metastases. Defined as lymphonodal involvement above the bifurcation of the iliac vessels or in inquinal regions and metastases resulting from hematogenous spread	through study completion, up to 5 years
Rate of patients with bladder preserved	Rate of patients with bladder preserved at the time of the biopsy of the tumour performed between one and two months after the last dose of atezolizumab	through study completion, up to 5 years
Rate of immediate or late salvage cystectomy	Immediate will be evaluated at the time of the biopsy of the tumour performed between one and two months after the last dose of atezolizumab and late will be evaluated during the follow-up	through study completion, up to 5 years
The safety profile and tolerability of the combination of atezolizumab with concurrent radiotherapy	Collection of any adverse events and serious adverse events	through study completion, up to 5 years

Collaborators and Investigators

• Sponsor: Spanish Oncology Genito-Urinary Group
• Collaborators: Roche Farma, S.A; Dynamic Science S.L.

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• Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, Hein A, Rote NS, Cope LM, Snyder A, Makarov V, Budhu S, Slamon DJ, Wolchok JD, Pardoll DM, Beckmann MW, Zahnow CA, Merghoub T, Chan TA, Baylin SB, Strick R. Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell. 2017 Apr 6;169(2):361. doi: 10.1016/j.cell.2017.03.036. No abstract available.
• 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.
• Ahmed KA, Stallworth DG, Kim Y, Johnstone PA, Harrison LB, Caudell JJ, Yu HH, Etame AB, Weber JS, Gibney GT. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol. 2016 Mar;27(3):434-41. doi: 10.1093/annonc/mdv622. Epub 2015 Dec 27.
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Helpful Links

• Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy testing in clinical trials. Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy testing in clinical trials. 2014
• Web page of the sponsor of the study

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2019
• Primary Completion (Anticipated): February 1, 2027
• Study Completion (Anticipated): May 1, 2027

Study Registration Dates

• First Submitted: November 26, 2019
• First Submitted That Met QC Criteria: December 2, 2019
• First Posted (Actual): December 4, 2019

Study Record Updates

• Last Update Posted (Actual): October 26, 2022
• Last Update Submitted That Met QC Criteria: October 25, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Antineoplastic Agents; Atezolizumab
• Other Study ID Numbers: SOGUG-2017-A-IEC(VEJ)-4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No