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

 Patients with MIUC fit to receive cisplatin.

 Study Design:

 The trial is designed as a non-comparative, open-label phase I/II study.

 Divided in two phases:

 The run In phase (I) and a phase II study. During the run-in phase, a limited number of
 patients (n=12-18) will be treated with durvalumab + ddMVAC or durvalumab + tremelimumab +
 ddMVAC (6-9 patients each). If the toxicity rate is acceptable (not higher than 2 out of 6 or
 3 out of 9 patients per arm) the study will continue as a randomized phase II study. During
 phase II, the efficacy and safety of durvalumab + ddMVAC and durvalumab + tremelimumab +
 ddMVAC

 Research hypothesis:

 Combination of checkpoint inhibitors (CPI), durvalumab ± tremelimumab, with neoadjuvant
 ddMVAC will improve the pathological complete response (pCR) rate in patients with
 muscle-invasive urothelial carcinoma (MIUC). No additional toxicity of the combination CPI +
 ddMVAC is expected.

 Investigational Product(s):

 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.

 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.

 Translational research:

 Mechanism of response/resistance to neoadjuvant treatment will be assessed by comparing
 molecular and immunological tumor profiles before treatment (transurethral resection tumor
 samples) and after treatment (cystectomy samples). In addition, circulating tumor DNA (ctDNA)
 and urine tumor DNA (utDNA) will be analysed during treatment (ctDNA and utDNA) and after
 surgery (ctDNA).

 Immunological profiles will be established using a specific metagene signature for major cell
 types of the tumor microenvironment and chemokines, cytokines and regulatory molecules , and
 will be validated using relevant markers by immunohistochemistry (IHC) on formalin-fixed
 paraffin-embedded (FFPE) tumor sections.

 Metabolomic profiling will also be conducted by analyzing metabolites present in urinary
 samples with a Proton-based nuclear magnetic resonance (1H-NMR), and correlations with
 prognosis, molecular profile or/and with immunological signature determined.

 Finally, correlations between tumor pathological factors (e.g., pTNM, nuclear grade, variant
 squamous differentiation or sarcomatoid dedifferentiation) and prognosis will be evaluated
 using IHC on FFPE tissue sections.

 Sample Size: Approximately 120 patients are planned to be included.
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, 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

 15. All micropapillary and plasmacytic forms, with or without squamous cell adenocarcinoma

 16. 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

 17. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

 18. Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1

 19. 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

 20. 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

 21. History of leptomeningeal carcinomatosis

 22. History of idiopathic pulmonary fibrosis, organizing pneumonia

 23. Serum albumin <25 g/L

 24. LVEF <50%

 25. 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

 26. 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

 27. 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 (e.g., 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 (e.g., CT scan premedication)

 28. 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

 29. 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 or 180 days after
 the last dose of durvalumab + tremelimumab combination therapy

 30. Known allergy or hypersensitivity to chimeric or humanized antibodies or fusion
 proteins, or to any of the study drugs or study drug excipients

 31. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical
 study regardless of treatment arm assignment

 32. 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 Procedures for withdrawal of incorrectly enrolled patients are presented in
 Section 4.3 If a patient withdraws from participation in the study, then his or her
 enrollment/randomization code cannot be reused. Withdrawn patients will not be
 replaced.