Durvalumab (MEDI4736) and TREmelimumab in NEOadjuvant Bladder Cancer Patients (DUTRENEO)

NCT03472274 | Completed Phase 2 DMC

• 2 other identifiers: DUTRENEO2017-002246-68
• Study Type: interventional
• Target: 101
• Locations: 1 country
• Sites: 11

Brief Summary

In the treatment of localized/locally advanced urothelial cancer, there are several questions that have not yet been resolved, such as the limited benefit of cisplatin-based chemotherapy in the adjuvant or neoadjuvant context, the difficulty in establishing which groups actually benefit from either perioperative treatment and what are the molecular markers that could help us predict the response to this treatment to allow a better selection of patients. On the other hand, not all patients are candidates for cisplatin-based chemotherapy and carboplatin is not comparable in activity, so there is an urgent need to find other drugs that may offer a therapeutic opportunity to these patients. In the context of metastatic disease, immunotherapy has been able to modify the natural history of this disease, administered as monotherapy, but the combination with double immune checkpoint inhibitors is also being evaluated with promising results. Even this therapeutic strategy is being advanced to the context of adjuvant and neoadjuvant treatment of urothelial tumors. In this sense, on the one hand, the present study, as a research in the neoadjuvant setting, constitutes the opportunity to define molecular phenotypes in bladder cancer since the design of this study will allow both, to evaluate the efficacy of the drug when the tumor is operable and to carry out an extensive analysis of biomarkers in the tumor tissue of these patients with an in-vivo evaluation of immune-based therapy activity. On the other hand, it allows to evaluate a strategy of double-immune checkpoint inhibitors that has already demonstrated activity in metastatic disease and, taking into account, the modest benefit of standard chemotherapy in the perioperative context: platinum-based neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer (MIBC) Modest increase in overall survival, but only a subset of eligible patients are eligible to receive it. In addition, radical cystectomy alone, in MIBC patients, presents a 5-year relapse rate of 10-50%.

Conditions

Bladder Cancer

Outcome Measures

Primary Outcomes (1)

• Antitumor activity

  Evidence of residual disease based on pathological review of the surgical specimen

  20 weeks

Secondary Outcomes (4)

• Overall Objective Response Rate

  20 weeks

• Disease Free Survival

  2 years

• Overall Survival

  2 years

• Incidence of Adverse Events

  20 weeks

Other Outcomes (2)

• Biomarkers of response

  20 weeks

• Biomarker expression

  20 weeks

Study Arms (2)

Cisplatin-based neoadjuvant chemotherapy

ACTIVE COMPARATOR

Patients allocated to the control arm will receive any of the following cisplatin based neoadjuvant treatment: Regimen 1: Gemcitabine + Cisplatin Regimen 2: Methotrexate + Vinblastine + Doxorubicin + Cisplatin Regimen 3: Gemcitabine + Paclitaxel + Cisplatin

Drug: Cisplatin-based neoadjuvant chemotherapy

Durvalumab plus Tremelimumab

EXPERIMENTAL

Patients randomized to experimental arma will receive 28-day treatment cycle x 3 cycles of Durvalumab + Tremelimumab 75 mg every 4 weeks

Drug: Durvalumab; Drug: Tremelimumab

Interventions

Durvalumab DRUG

Durvalumab 1500 mg every 4 weeks x 3 cycles

Durvalumab plus Tremelimumab

Tremelimumab DRUG

Tremelimumab 75 mg every 4 weeks x 3 cycles

Durvalumab plus Tremelimumab

Cisplatin-based neoadjuvant chemotherapy DRUG

Regimen 1: 21-day treatment cycle x 3 cycles. * Gemcitabine 1,000-1,200 mg/m2 intravenously on days 1 and 8 every 21 days. * Cisplatin 70 mg/m2 intravenously on day 1 every 21 days. Regimen 2: ddMVAC 14-day treatment cycle x 4 doses. * Methotrexate 30mg/m2 intravenously on day 1 * Vinblastine 3mg/m2 intravenously on day 2 * Doxorubicin 30mg/m2 intravenously on day 2 * Cisplatin 70mg/m2 intravenously on day 2 Granulocyte colony-stimulating factor (G-CSF) for 7 consecutive days (days 4 through 10). Regimen 3: 21-day treatment cycle x 3 cycle * Gemcitabine 1,000 mg/m2 intravenously on day 1 and 8 * Paclitaxel 80 mg/m2 intravenously on day 1 and 8 * Cisplatin 70mg/m2 intravenously on day 1

Also known as: Standard of care (SoC)

Cisplatin-based neoadjuvant chemotherapy

Eligibility Criteria

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

You may qualify if:

• Male and female subjects; age ≥ 18 years at the time of study entry.
• Subjects must provide written informed consent prior to performance of any protocol-related procedures, including screening evaluations and must be willing to comply with treatment and follow up.
• Subjects must have histologic documentation of transitional cell carcinoma of the urothelium (including the urinary bladder, ureter, urethra and renal pelvis) of the urinary tract (cystoscopy and biopsy or positive cytology).
• Patients must have confirmed cT2-T4 N0-1 M0 (TNM classification).
• Archival tumour samples for biomarker research in formalin-fixed and paraffin-embedded blocks.
• Body weight \>30kg
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy of at least 12 weeks
• Adequate organ function as determined by:
• a) Hematological (without growth factor or transfusion support within 28 days prior to first dose of investigational product)
• Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L).
• Platelets ≥ 100,000/mm3 (≥ 100 GI/L)
• Hemoglobin ≥ 9 g/dL (≥ 90 g/L)
• Hepatic:
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN.

You may not qualify if:

• Histology of pure adenocarcinoma, pure squamous cell carcinoma, or predominant small cell carcinoma or sarcomatoid features in the tumor sample.
• Evidence of any metastatic lesion outside the primary tumour site identified in the radiological evaluation.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection).
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent.
• Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
• Previous therapy with PD-1, PD-L1 or CTLA-4 inhibitors, including durvalumab and tremelimumab.
• Any concurrent chemotherapy, immunotherapy (IMT), or biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable.
• History of severe allergic reactions (ie, Grade 4 allergy, anaphylactic reaction from which the subject did not recover within 6 hours of institution of supportive care) to any unknown allergens or any components of the study drug formulations.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone

Sponsors & Collaborators

• Fundacion CRIS de Investigación para Vencer el Cáncer: lead
• AstraZeneca: collaborator
• Apices Soluciones S.L.: collaborator

Study Sites (11)

ICO Badalona

Badalona, Spain

Location

Hospital Clinic

Barcelona, Spain

Location

Hospital de la Santa Creu i Sant Pau

Barcelona, Spain

Location

ICO L'Hospitalet

L'Hospitalet de Llobregat, Spain

Location

Hospital 12 de Octubre

Madrid, Spain

Location

Hospital Clinico San Carlos

Madrid, Spain

Location

Hospital Ramon y Cajal

Madrid, Spain

Location

Hospital Universitario La Paz

Madrid, Spain

Location

MD Anderson Cancer Center

Madrid, Spain

Location

Hospital Marqués de Valdecilla

Santander, Spain

Location

Instituto Valenciano de Oncología

Valencia, Spain

Location

Related Publications (1)

• Sibai M, Cervilla S, Grases D, Musulen E, Lazcano R, Mo CK, Davalos V, Fortian A, Bernat A, Romeo M, Tokheim C, Barretina J, Lazar AJ, Ding L; DUTRENEO Study Investigators; Grande E, Real FX, Esteller M, Bailey MH, Porta-Pardo E. The spatial landscape of cancer hallmarks reveals patterns of tumor ecological dynamics and drug sensitivity. Cell Rep. 2025 Feb 25;44(2):115229. doi: 10.1016/j.celrep.2024.115229. Epub 2025 Jan 24.

  PMID: 39864059 DERIVED

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

durvalumab; tremelimumab; Standard of Care

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Enrique Grande, MD

  MD Anderson Cancer Center Madrid

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: March 14, 2018
• First Posted: March 21, 2018
• Study Start: October 25, 2018
• Primary Completion: April 30, 2021
• Study Completion: April 12, 2023
• Last Updated: April 13, 2023

Record last verified: 2023-04

Locations

ES (11)