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

• ClinicalTrials.gov Identifier: NCT04186013
• Recruitment Status: Active, not recruiting
• First Posted: December 4, 2019
• Last Update Posted: October 26, 2022
• Sponsor: Spanish Oncology Genito-Urinary Group
• Collaborators: Roche Farma, S.A; Dynamic Science S.L.
• Information provided by (Responsible Party): Spanish Oncology Genito-Urinary Group

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Bladder Cancer	Drug: Atezolizumab Injection [Tecentriq]; Radiation: External Beam Radiation Therapy (EBRT)	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy of Atezolizumab Concurrent With Radiotherapy in Patients With Muscle-invasive Bladder cáncer (Study ATEZOBLADDERPRESERVE)
• Actual Study Start Date: September 18, 2019
• Estimated Primary Completion Date: February 2027
• Estimated Study Completion Date: May 2027

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Pathological complete response [ Time Frame: After the end of the treatment (16 weeks) ]
   Response of grade 5 according to Miller and Payne criteria

Secondary Outcome Measures :

1. Overall survival [ Time Frame: through study completion, up to 5 years ]
   Time from the date of the beginning of protocol therapy to the date of death due to any cause
2. Disease specific survival [ Time Frame: through study completion, up to 5 years ]
   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
3. Disease free survival [ Time Frame: through study completion, up to 5 years ]
   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
4. Bladder-intact disease-free survival [ Time Frame: through study completion, up to 5 years ]
   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
5. Muscle invasive and non-muscle invasive local failure [ Time Frame: through study completion, up to 5 years ]
   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
6. Rate of distant metastases [ Time Frame: through study completion, up to 5 years ]
   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
7. Rate of patients with bladder preserved [ Time Frame: through study completion, up to 5 years ]
   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
8. Rate of immediate or late salvage cystectomy [ Time Frame: through study completion, up to 5 years ]
   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
9. The safety profile and tolerability of the combination of atezolizumab with concurrent radiotherapy [ Time Frame: through study completion, up to 5 years ]
   Collection of any adverse events and serious adverse events

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

Spain

Althaia Xarxa Assintencial

Manresa, Barcelona, Spain, 08243

Consorci Corporació Sanitària Parc Taulí

Sabadell, Barcelona, Spain, 08208

Hospital Universitario Sant Joan de Reus

Reus, Tarragona, Spain, 43204

Hospital Clínico Universitario San Cecilio

Granada, Spain, 18016

Hospital Universitario Lucus Augusti

Lugo, Spain, 27003

Hospital Universitario La Princesa

Madrid, Spain, 28006

Hospital HM Sanchinarro

Madrid, Spain, 28050

Complejo Hospitalario Universitario Ourense

Orense, Spain, 32005

Hospital Universitario Central de Asturias

Oviedo, Spain, 33011

Hospital Arnau de Vilanova

Valencia, Spain, 6015

Sponsors and Collaborators

Spanish Oncology Genito-Urinary Group

Roche Farma, S.A

Dynamic Science S.L.

More Information

Additional Information:

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 

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Sistigu A, Yamazaki T, Vacchelli E, Chaba K, Enot DP, Adam J, Vitale I, Goubar A, Baracco EE, Remedios C, Fend L, Hannani D, Aymeric L, Ma Y, Niso-Santano M, Kepp O, Schultze JL, Tuting T, Belardelli F, Bracci L, La Sorsa V, Ziccheddu G, Sestili P, Urbani F, Delorenzi M, Lacroix-Triki M, Quidville V, Conforti R, Spano JP, Pusztai L, Poirier-Colame V, Delaloge S, Penault-Llorca F, Ladoire S, Arnould L, Cyrta J, Dessoliers MC, Eggermont A, Bianchi ME, Pittet M, Engblom C, Pfirschke C, Preville X, Uze G, Schreiber RD, Chow MT, Smyth MJ, Proietti E, Andre F, Kroemer G, Zitvogel L. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med. 2014 Nov;20(11):1301-9. doi: 10.1038/nm.3708. Epub 2014 Oct 26.

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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

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Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. doi: 10.1016/S0140-6736(16)00587-0. Epub 2016 Mar 10.

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• Responsible Party: Spanish Oncology Genito-Urinary Group
• ClinicalTrials.gov Identifier: NCT04186013
• Other Study ID Numbers: SOGUG-2017-A-IEC(VEJ)-4
• First Posted: December 4, 2019
• Last Update Posted: October 26, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Urinary Bladder Neoplasms; 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; Atezolizumab; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Antineoplastic Agents