Durvalumab Plus Tremelimumab With Concurrent Radiotherapy for Localized Muscle Invasive Bladder Cancer Treated With a Selective Bladder Preservation Approach

NCT03702179 | Completed Phase 2 Results DMC

• 1 other identifier: SOGUG-2017-A-IEC(VEJ)-1
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 7

Brief Summary

Combined-modality treatment of localized muscle invasive bladder cancer including transurethral resection (TUR), radiotherapy and dual checkpoint inhibition immunotherapy could achieve pathological complete response in some patients. These patients could avoid to undergone radical surgery with radical cystectomy and preserve their bladder, without the side-effects associated with chemotherapy and surgery. This study has been design to determine the efficacy of durvalumab plus tremelimumab with concurrent radiotherapy in terms of pathological response rate in patients with localized muscle invasive bladder cancer treated with bladder preservation intent.

Conditions

Invasive Bladder Cancer

Keywords

localized muscle invasive bladder cancer; bladder preservation; durvalumab; tremelimumab; radiotherapy

Outcome Measures

Primary Outcomes (1)

• Proportion of Patients With Pathological Response

  Pathological response is defined as the absence of muscle- invasive bladder cancer at post-treatment biopsy (≤cT1). Cystoscopy and bladder biopsy six weeks since the end of radiotherapy.

  12 weeks

Secondary Outcomes (7)

• Rate of Patients With Bladder Preserved

  24 months

• Rate of Immediate Salvage Cystectomies

  24 months

• Rate of Late Salvage Cystectomies

  24 months

• Survival With Bladder Preserved Free of Tumor

  24 months

• Disease-free Survival

  24 months

Study Arms (1)

Durvalumab + Tremelimumab

EXPERIMENTAL

The treatment consisted of initial TUR of the tumor, with multiple random biopsies of normal-appearing bladder urothelium, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for a total of 3 doses. Two weeks after the initiation of immunotherapy, normofractionated external-beam radiotherapy with high-energy photons will be started. Radiotherapy will be administered concurrently with immunotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder.

Drug: Durvalumab; Drug: Tremelimumab; Radiation: Radiotherapy

Interventions

Durvalumab DRUG

All patients will receive durvalumab (MEDI4736) (1500mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 3 doses/cycles each, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. If a patient's weight falls to 30kg or below the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W and 1mg/kg tremelimumab Q4W until the weight improves to \>30 kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500mg plus tremelimumab 75 mg Q4W.

Also known as: MEDI4736

Durvalumab + Tremelimumab

Tremelimumab DRUG

All patients will receive durvalumab (MEDI4736) (1500mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 3 doses/cycles each, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. If a patient's weight falls to 30kg or below the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W and 1mg/kg tremelimumab Q4W until the weight improves to \>30 kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500mg plus tremelimumab 75 mg Q4W.

Durvalumab + Tremelimumab

Radiotherapy RADIATION

Radiotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder.

Durvalumab + Tremelimumab

Eligibility Criteria

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

You may qualify if:

• Patients must have signed the informed consent prior to undergoing any study procedure.
• Patients must be 18 years of age or older.
• Patients must have Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
• A paraffin-embedded tumor sample must be available for the associate molecular study.
• Body weight \>30 Kg.
• Adequate normal organ and marrow function.
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre- menopausal patients.
• Patient is willing and able to comply with the protocol for the duration of the study.

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both Sponsor staff and/or staff at the study site).
• Participation in another clinical study with an investigational product during the last 30 days.
• Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Previous treatment with radiotherapy to the bladder, systemic chemotherapy or immune checkpoint inhibitors. Prior intravesical Bacillus Calmette-Guérin (BCG) treatment for non-muscle invasive bladder cancer is allowed, 28 days prior to study.
• Presence of regional lymph node or metastatic extension of the disease.
• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) \<\<for durvalumab monotherapy and durvalumab + tremelimumab combination studies this criterion can be removed. For durvalumab ±tremelimumab in combination with an agent with pro-arrhythmic potential or where effect of the combination on QT is not known if this criterion should be retained. Patient safety and the cardiac ECG should be consulted as needed\>\>.
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
• Any concurrent chemotherapy, investigational product (IP) other than studied in this protocol, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• History of allogenic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders.
• Uncontrolled intercurrent illness.
• History of another primary malignancy.
• History of active primary immunodeficiency.
• Active infection.

Sponsors & Collaborators

• Spanish Oncology Genito-Urinary Group: lead
• AstraZeneca: collaborator
• MFAR: collaborator

Study Sites (7)

Instituto Catalán de Oncología Badalona

Badalona, Barcelona, 08024, Spain

Location

Centro Oncológico de Galicia

A Coruña, Spain

Location

Instituto Catalán de Oncología L'Hospitalet

Barcelona, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 08024, Spain

Location

H.U. Virgen del Rocío

Seville, 41013, Spain

Location

Hospital Universitario y Politécnico La Fe

Valencia, Spain

Location

Instituto Valenciano de Oncología

Valencia, Spain

Location

MeSH Terms

Interventions

durvalumab; tremelimumab; Radiotherapy

Intervention Hierarchy (Ancestors)

Therapeutics

Results Point of Contact

• Title: A contact designated by the Sponsor
• Organization: SOGUG

secretaria@sogug.es

+34671422325

Study Officials

• Xavier García del Muro, M.D.

  Instituto Catalán de Oncología L'Hospitalet

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study will be conducted using a two-stage sequential design. Using the assumption that the treatment would be considered ineffective if it had a response proportion similar to radiotherapy alone (P0: 0.5) but would be of considerable interest if it had a response proportion of 70% of more (P1: 0.7), the sample size requirement is 12 patients for the first stage and 20 additional patients for the second stage. Six or more responses in the first stage were required for continuation to second stage accrual. The study was planned to have a type I error of 0.10 and a power of 80% in a one sided test.

Study Record Dates

• First Submitted: October 8, 2018
• First Posted: October 10, 2018
• Study Start: November 19, 2018
• Primary Completion: September 29, 2020
• Study Completion: August 16, 2022
• Last Updated: December 5, 2024
• Results First Posted: December 5, 2024

Record last verified: 2023-08

Locations

ES (7)