NEoadjuvant Dose-dense MVAC In cOmbination With Durvalumab and Tremelimumab in Muscle-invasive Urothelial Carcinoma

NCT03549715 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: NEMIO
• Study Type: interventional
• Target: 121
• Locations: 1 country
• Sites: 15

Brief Summary

This is an open label, phase I/II clinical trial to evaluate the efficacy and safety of 2 cycles of durvalumab without (Arm A) or with (Arm B) tremelimumab in association with ddMVAC as neoadjuvant therapy in patients with MIUC.

Conditions

Infiltrating Bladder Urothelial Carcinoma

Outcome Measures

Primary Outcomes (2)

• Toxicity Grade

  Grade ≥ 3 treatment related toxicity rate

  68 months

• pathologic complete response

  pCR rate after ddMVAC + durvalumab ± tremelimumab period

  1 year

Secondary Outcomes (4)

• Disease-Free Survival (DFS)

  2 years

• Overall Survival (OS)

  2 years

• Adverse Events (AEs).

  68 months

• Pathologic downstaging

  During procedure

Other Outcomes (3)

• Molecular profile

  2 years

• Factors of pCR

  1 year

• Immunological signature

  2 years

Study Arms (2)

ARM A: durvalumab + ddMVAC

EXPERIMENTAL

Durvalumab + ddMVAC Durvalumab 1500 mg IV D1 every 28 days Durvalumab will be administered at the hospital every 28 days prior to administration of ddMVAC on D1.

Drug: Durvalumab; Drug: MVAC Protocol

ARM B: durvalumab + tremelimumab+ ddMVAC

EXPERIMENTAL

durvalumab + tremelimumab + ddMVAC Tremelimumab 75 mg IV D1 every 28 days Tremelimumab will be administered first, with durvalumab infusion starting approximately 1 hour (maximum 2 hours) after the end of the tremelimumab infusion. Infusion of ddMVAC will start approximately 1 hour after completion of durvalumab.

Drug: Durvalumab; Drug: Tremelimumab; Drug: MVAC Protocol

Interventions

Durvalumab DRUG

1500 mg IV D1 every 28 days (2 doses for each patient)

Also known as: MEDI4736

ARM A: durvalumab + ddMVAC; ARM B: durvalumab + tremelimumab+ ddMVAC

Tremelimumab DRUG

75 mg IV D1 every 28 days ((2 doses for each patient)

Also known as: CP-675,206

ARM B: durvalumab + tremelimumab+ ddMVAC

MVAC Protocol DRUG

1. Methotrexate 30 mg/m2 IV D1 2. Vinblastine 3 mg/m2 IV D1 3. Adriamycin (doxorubicin) 30 mg/m2 IV D1 4. Cisplatin 70 mg/m2 IV D1

Also known as: ddMVAC

ARM A: durvalumab + ddMVAC; ARM B: durvalumab + tremelimumab+ ddMVAC

Eligibility Criteria

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

You may qualify if:

• Written informed consent and any locally required authorization (e.g., EU Data Privacy Directive in the EU) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
• Age ≥18 years at time of study entry
• Histologically confirmed MIUC (also termed TCC) of the bladder. Patients with mixed histologies are required to have a dominant transitional cell pattern (urothelial carcinoma must be \> 50%)
• Localized MIUC of the bladder with clinical stage T2-T4a and ≤N1 disease ( the single lymph node must be \< 15 mm (short axis) on imaging
• Patients with urothelial carcinoma of the prostatic urethra
• Bodyweight \>45kg
• Patients eligible for cisplatin-based neoadjuvant chemotherapy, including:
• Creatinine clearance (CL) \>60 mL/min based on the Modification of Diet in Renal Disease Study (MDRD) formula
• Cardiac left ventricular ejection fraction (LVEF) ≥50%
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absence of metastasis, as confirmed by a negative baseline CT or MRI scan of the pelvis, abdomen, and chest no more than 4 weeks prior to randomization. Patients with clinical stage N1 disease are eligible if the single lymph node measures ≤2 cm in greatest dimension.
• Adequate organ and marrow function as defined below (obtained within 14 days prior to the first study treatment):
• Hemoglobin ≥10.0 g/dL (patients may be transfused to meet this criterion)
• Absolute neutrophil count (ANC) ≥1500 cells/μL (without G-CSF support within 2 weeks prior to Cycle 1, Day 1)
• WBC counts \>2500/µL

You may not qualify if:

• Urothelial carcinoma of the upper tract
• Any approved anti-cancer therapy for urothelial carcinoma, including chemotherapy, or immunotherapy prior to initiation of study treatment. Of note, previous intravesical BCG injections are allowed if administered for non-muscle invasive urothelial carcinoma
• Primary chemoradiation for bladder preservation for urothelial carcinoma of the bladder
• Impaired renal function (glomerular filtration rate \[GFR\]\<60 mL/min); GFR should be assessed by calculation from serum/plasma creatinine (MDRD formula)
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
• Grade 2 or greater hearing loss that contraindicates cisplatin use. Threshold shift of \>25 decibel averaged at 2 contiguous test frequencies in least one ear.
• Exception: Patients with Grade 2 hearing loss diagnosed on the audiogram that are asymptomatic (no complain of hearing loss and no tinnitus) can be enrolled in the study.
• Grade 2 or greater peripheral neuropathy
• Oral anticoagulation treatment (vitamin K antagonist should be replaced by low-molecular-weight heparin).
• Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug
• 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
• Any concurrent chemotherapy, investigational product, 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) other than for diagnosis within 28 days prior to Cycle 1
• History of prior organ transplantation, including stem cell allografting
• History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and type I diabetes mellitus on stable dose of insulin may be eligible for this study

Sponsors & Collaborators

• Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie: lead

Study Sites (15)

Hôpital Saint André, CHU de Bordeaux

Bordeaux, 33075, France

Location

Sasu Roc37

Chambray-lès-Tours, 37170, France

Location

CHU Henri-Mondor

Créteil, 94000, France

Location

Centre Leon Berard

Lyon, 69008, France

Location

Institut Paoli Calmettes

Marseille, 13009, France

Location

Centre Antoine Lacassagne

Nice, 06100, France

Location

Groupe Hospitalier Pitié-Salpetrière

Paris, 75013, France

Location

Institut Mutualiste Montsouris

Paris, 75014, France

Location

Hôpital Cochin

Paris, 75679, France

Location

Centre Eugène Marquis

Rennes, 35042, France

Location

Hia Begin

Saint-Mandé, 94160, France

Location

Hôpitaux universitaires de Strasbourg

Strasbourg, 67000, France

Location

Institut Claudius Regaud

Toulouse, 31059, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

Hôpital Européen Georges Pompidou

Paris, Île-de-France Region, 75015, France

Location

Related Publications (1)

• Thibault C, Elaidi R, Vano YA, Rouabah M, Braychenko E, Helali I, Audenet F, Oudard S. Open-label phase II to evaluate the efficacy of NEoadjuvant dose-dense MVAC In cOmbination with durvalumab and tremelimumab in muscle-invasive urothelial carcinoma: NEMIO. Bull Cancer. 2020 Jun;107(5S):eS8-eS15. doi: 10.1016/S0007-4551(20)30281-2.

  PMID: 32620213 DERIVED

MeSH Terms

Interventions

durvalumab; tremelimumab; M-VAC protocol

Study Officials

• Constance THIBAULT, MD

  Hôpital Européen Georges Pompidou, Oncology department of Pr Stéphane OUDARD

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The sample size will be balanced between 2 arms. Initially, 12 patients (6 in each arm) will be included and randomized between durvalumab + ddMVAC (ARM A) or durvalumab + tremelimumab + ddMVAC (ARM B)

Study Record Dates

• First Submitted: May 15, 2018
• First Posted: June 8, 2018
• Study Start: December 6, 2018
• Primary Completion: June 1, 2024
• Study Completion: September 1, 2025
• Last Updated: March 6, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (15)