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

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ClinicalTrials.gov Identifier: NCT03549715
Recruitment Status : Recruiting
First Posted : June 8, 2018
Last Update Posted : May 10, 2019
Sponsor:
Information provided by (Responsible Party):
Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie

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.

Condition or disease Intervention/treatment Phase
Infiltrating Bladder Urothelial Carcinoma Drug: Durvalumab Drug: Tremelimumab Drug: MVAC Protocol Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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)
Masking: None (Open Label)
Masking Description: Open label
Primary Purpose: Treatment
Official Title: NEoadjuvant Dose-dense MVAC In cOmbination With Durvalumab (MEDI4736) and Tremelimumab in Muscle-invasive Urothelial Carcinoma
Actual Study Start Date : December 6, 2018
Estimated Primary Completion Date : November 2023
Estimated Study Completion Date : November 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: ARM A: durvalumab + ddMVAC
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
1500 mg IV D1 every 28 days (2 doses for each patient)
Other Name: MEDI4736

Drug: MVAC Protocol
  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
Other Name: ddMVAC

Experimental: ARM B: durvalumab + tremelimumab+ ddMVAC

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
1500 mg IV D1 every 28 days (2 doses for each patient)
Other Name: MEDI4736

Drug: Tremelimumab
75 mg IV D1 every 28 days ((2 doses for each patient)
Other Name: CP-675,206

Drug: MVAC Protocol
  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
Other Name: ddMVAC




Primary Outcome Measures :
  1. Toxicity Grade [ Time Frame: 38 months ]
    Grade ≥ 3 treatment related toxicity rate

  2. pathologic complete response [ Time Frame: 1 year ]
    pCR rate after ddMVAC + durvalumab ± tremelimumab period


Secondary Outcome Measures :
  1. Disease-Free Survival (DFS) [ Time Frame: 1 year ]
    To evaluate the 1-year disease-free survival (DFS) rate.

  2. Overall Survival (OS) [ Time Frame: 1 year ]
    To evaluate the 1-year overall survival (OS) rate

  3. Adverse Events (AEs). [ Time Frame: 38 months ]
    To evaluate the incidence of adverse events (AEs).

  4. Pathologic downstaging [ Time Frame: During procedure ]
    To evaluate the pathologic downstaging rate (defined as the presence of residual tumor ≤T1 on cystectomy, excluding T0).


Other Outcome Measures:
  1. Molecular profile [ Time Frame: 1 year ]
    To determine changes in the molecular profile and immunological signature of the tumor after treatment compared with before treatment.

  2. Factors of pCR [ Time Frame: 1 year ]
    To identify predictive factors of pCR response to treatment.

  3. Immunological signature [ Time Frame: 1 year ]
    To determine changes in the immunological signature of the tumor after treatment compared with before treatment.



Information from the National Library of Medicine

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

Inclusion Criteria:

  1. 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
  2. Age ≥18 years at time of study entry
  3. 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%)
  4. 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
  5. Patients with urothelial carcinoma of the prostatic urethra
  6. Bodyweight >45kg
  7. 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%
  8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  9. 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.
  10. 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
    • Platelet count ≥100,000/µL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
    • Serum bilirubin ≤1.0 x institutional upper limit of normal (ULN). Patients with known Gilbert disease who have serum bilirubin level ≤3 x ULN may be enrolled.
    • AST, ALT, and alkaline dehydrogenase ≤2.5 x ULN
    • Partial thromboplastin time/prothrombin time (PTT/PT) ≤1.5 x ULN or international normalized ratio (INR) <1.7 x ULN
  11. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

    • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
    • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  12. Women of childbearing potential and non-sterilized males who are sexually active with a female partner of childbearing potential must be willing to use contraceptive methods during the treatment period and for at least 6 months after the last dose of treatment
  13. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

Exclusion Criteria:

  1. Urothelial carcinoma of the upper tract
  2. 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
  3. Primary chemoradiation for bladder preservation for urothelial carcinoma of the bladder
  4. Impaired renal function (glomerular filtration rate (GFR)<60 mL/min); GFR should be assessed by calculation from serum/plasma creatinine (MDRD formula)
  5. 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
  6. 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.
  7. Grade 2 or greater peripheral neuropathy
  8. Oral anticoagulation treatment (vitamin K antagonist should be replaced by low-molecular-weight heparin)
  9. 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
  10. 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
  11. 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
  12. Major surgical procedure (as defined by the Investigator) other than for diagnosis within 28 days prior to Cycle 1
  13. History of prior organ transplantation, including stem cell allografting
  14. 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, Sjogren'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
  15. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  16. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
  17. Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
  18. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina
  19. History of another primary malignancy within 3 years prior to Cycle 1, Day 1, except for:

    • Localized low-risk prostate cancer (defined as Stage ≤T2b, Gleason score ≤7, and prostate-specific antigen [PSA] at prostate cancer diagnosis ≤20 ng/mL [if measured]) treated with curative intent and without PSA recurrence
    • Low-risk prostate cancer (defined as Stage T1/T2a, Gleason score <7, and PSA ≤10 ng/mL) who are treatment-naive and undergoing active surveillance
    • Patients with malignancies of a risk of metastasis/death (e.g., risk of metastasis or death <5% at 5 years) are eligible after investigator's approval if they meet both of the following criteria: Malignancy treated with expected curative intent, and no evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers
  20. History of leptomeningeal carcinomatosis
  21. History of idiopathic pulmonary fibrosis, organizing pneumonia
  22. Serum albumin <25 g/L
  23. LVEF <50%
  24. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 electrocardiograms (ECGs) within 15 minutes at 5 minutes apart
  25. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if PCR is negative for HCV RNA
  26. 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 ( intra articular injection)
    • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    • Steroids as premedication for hypersensitivity reactions (CT scan premedication)
  27. Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment. Note: Patients, if enrolled, should not receive live vaccine whilst receiving study treatment and for up to 30 days after the last dose of study treatment
  28. Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or180 days after the last dose of durvalumab + tremelimumab combination therapy
  29. Known allergy or hypersensitivity to chimeric or humanized antibodies or fusion proteins, or to any of the study drugs or study drug excipients
  30. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment
  31. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that, in the opinion of the Investigator, makes the patient unsuitable for participation in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03549715


Contacts
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Contact: Reza ELAIDI, PhD 00 33 1 56 09 23 40 reza-thierry.elaidi-ext@aphp.fr
Contact: Mouna ROUABAH 00 33 1 56 09 50 16 mouna.rouabah-ext@aphp.fr

Locations
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France
Hôpital Européen Georges Pompidou Recruiting
Paris, Ile De France, France, 75015
Contact: Constance THIBAULT, MD    00 33 1 56 09 59 92    constance.thibault@aphp.fr   
Principal Investigator: Constance THIBAULT, MD         
Hôpital Saint André, CHU de Bordeaux Active, not recruiting
Bordeaux, France, 33075
Sasu Roc37 Not yet recruiting
Chambray Les Tours, France, 37170
Contact: Pierre COMBE, MD         
CHU Henri-Mondor Active, not recruiting
Créteil, France, 94000
Centre Leon Berard Recruiting
Lyon, France, 69008
Contact: Aude FLECHON, MD         
Institut Paoli Calmettes Not yet recruiting
Marseille, France, 13009
Contact: Gwaenaelle Gravis, MD       GRAVISG@marseille.fnclcc.fr   
Centre Antoine Lacassagne Recruiting
Nice, France, 06100
Contact: Delphine BORCHIELLINI, MD       Delphine.BORCHIELLINI@nice.unicancer.fr   
Groupe Hospitalier Pitié-Salpetrière Not yet recruiting
Paris, France, 75013
Contact: Aurelien Gobert, MD       aurelien.gobert@aphp.fr   
Institut Mutualiste Montsouris Not yet recruiting
Paris, France, 75014
Contact: Mostefa Bennamoun, MD       Mostefa.Bennamoun@imm.fr   
Hôpital Cochin Recruiting
Paris, France, 75679
Contact: Olivier HUILLARD, MD       olivier.huillard@aphp.fr   
Centre Eugene Marquis Active, not recruiting
Rennes, France, 35042
Hia Begin Active, not recruiting
Saint-Mandé, France, 94160
Hôpitaux universitaires de Strasbourg Recruiting
Strasbourg, France, 67000
Contact: Philippe BARTHELEMY, MD       philippe.barthelemy@chru-strasbourg.fr   
Institut Claudius Regaud Recruiting
Toulouse, France, 31059
Contact: Damien POUESSEL, MD         
Institut Gustave Roussy Not yet recruiting
Villejuif, France, 94805
Contact: Yohann LORIOT, MD         
Sponsors and Collaborators
Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
Investigators
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Principal Investigator: Constance THIBAULT, MD Hôpital Européen Georges Pompidou, Oncology department of Pr Stéphane OUDARD

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Responsible Party: Association Pour La Recherche des Thérapeutiques Innovantes en Cancérologie
ClinicalTrials.gov Identifier: NCT03549715     History of Changes
Other Study ID Numbers: NEMIO
First Posted: June 8, 2018    Key Record Dates
Last Update Posted: May 10, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No plan to share

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Durvalumab
Tremelimumab
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs