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Study Cabozantinib plus Durvalumab in patients with advanced and chemotherapy-treated bladder carcinoma, of urothelial and non-urothelial histology: an open-label, phase 2, proof-of-concept trial - ARCADIA

Studio Clinico

Patologia: Carcinoma della vescica

Osservazionale-Sperimentale: Sperimentale

Monocentrico-Multicentrico: Monocentrico

Randomizzato: No

Fase di studio: II

Richiesta mandatoria di tessuto: 

Linee di trattamento: Seconda linea, Terza/N linea

Criteri di inclusione: 

- Written informed consent.
- Age ≥18 years.
- Body weight >30kg
- Male and female gender.
- Histologically-confirmed diagnosis of UC or variant histologies (e.g. squamous cell carcinoma, adenocarcinoma, micropapillary tumors, BUT excluding pure small cell carcinoma) of the bladder or the urothelium.
- Either bladder, urethral, or upper tract primary tumor will be allowed.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- Life expectancy of at least 12 weeks.
- Availability of tumor tissue for PD-L1 IHC assay.
- Measurable and non-measurable disease will be included (e.g. patients with bone metastases only will be allowed for inclusion).
- Failure of 1 or 2 cisplatin-based conventional chemotherapy regimens for metastatic disease (2nd-to-3rd line only).
- Neoadjuvant/adjuvant regimens will be counted provided that a relapse occurred within 6 months of the last cycle of chemotherapy.
- Adequate end-organ function tests (see the full protocol).
- Recovery to baseline or ≤ Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) v4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
- Ability to swallow tablets
- Contraception for sexually active fertile patients and their partners. Of note, a barrier method is recommended in addition to the use of steroid hormonal contraceptives, because the effects of cabozantinib on the pharmacokinetics of the latter are unknown.

Criteri di esclusione: 

- Patients taking regular oral steroids, above the allowed limit of 10mg/day methylprednisolone or analogues, for any reason. Patients must not have had steroids for 28 days prior to study entry.
- Malignancies other than bladder carcinoma within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA < 10 ng/mL undergoing active surveillance and treatment naive).
- Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results.
- Active or untreated CNS metastases as determined by computed tomography (CT) or magnetic resonance imaging evaluation during screening and prior radiographic assessments.
- Patients with treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:
- Evaluable or measurable disease outside the CNS
- No metastases to midbrain, pons, medulla, or within 10 mm of the optic apparatus (optic nerves and chiasm)
- No history of intracranial or spinal cord hemorrhage
- No ongoing requirement for corticosteroid as therapy for CNS disease; anti-convulsants at a stable dose are allowed
- No evidence of significant vasogenic edema
- No stereotactic radiation, whole-brain radiation or neurosurgical resection within 4 weeks prior to Cycle 1, Day 1
- Radiographic demonstration of interim stability (i.e., no progression) between the completion of CNSdirected therapy and the screening radiographic study
- Screening CNS radiographic study ≥ 4 weeks since completion of radiotherapy or surgical resection and ≥ 2 weeks since discontinuation of corticosteroids
- Pregnant female patients. All female patients of childbearing potential with a positive pregnancy test within 2 weeks prior to the first dose of study treatment will be excluded from the study.
- Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina.
- Uncontrolled hypertension, stroke or other ischemic or thromboembolic event (DVT, PE) within 6 months before first dose of cabozantinib.
- Severe infections within 4 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
- Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis. Complete wound healing from major surgery must have occurred 1 month before inclusion and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before inclusion. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
- Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to enrolment (patients receiving prophylactic antibiotics, e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease, are eligible).
- Concomitant anticoagulation with oral anticoagulants or platelet inhibitors.
- 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, unless on a stable dose of thyroid replacement hormone.
- Patients with uncontrolled Type 1 diabetes mellitus.
- Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while on study.
- History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted).
- Positive test for HIV.
- Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
- Patients with active tuberculosis.
- Gastrointestinal disorders likely to interfere with absorption of the study drug (e.g. partial bowel obstruction or malabsorption).
- Subjects with gastrointestinal disorders associated with a high risk of perforation of fistula formation.
- Subjects with active peptic ulcer or with a history of clinically significant GI bleeding within 12 weeks
before the first dose of study treatment.
- Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agents.
- Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study.
- Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrolment.
- Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]−2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment.

Schema di trattamento: 

Subjects will receive 1500mg durvalumab (MEDI4736) via IV infusion Q4W until confirmed disease progression unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.
Cabozantinib will be assumed orally, daily, at the dose of 40 mg continuously until there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.

Trattamento sperimentale: 

Cabozantinib + Durvalumab

Trattamento di controllo: 


Obiettivi primari dello studio: 

To assess the clinical activity of the combination of cabozantinib and durvalumab in a population of chemotherapy-treated, metastatic urothelial carcinoma.

Obiettivi secondari dello studio: 

- To determine the safety and translational results of the combination of cabozantinib and durvalumab in urothelial carcinoma.
- To determine potential biomarkers of activity of the combination of cabozantinib and durvalumab in metastatic urothelial carcinoma.

Centri partecipanti

Nord Italia

IRCCS Istituto Nazionale dei Tumori
Via Venezian 1 - 20133 Milano - MI

Riferimento: Dr.ssa Patrizia Giannatempo
Telefono: 0223902402

Informazioni Generali


Numero di iscrizione a registro: NCT03824691

Data di inserimento: 27.08.2021


Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Principal Investigator ITALIA

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Riferimento: Dr.ssa Patrizia Giannatempo

Telefono: 0223902402


Localita: Milano


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