Locally Advanced or Metastatic Urothelial Carcinoma Clinical Trial
Official title:
Phase II, Multicenter, Non-randomized, Single-arm, Open-label Trial of Atezolizumab in Combination of Split-doses of Gemcitabine Plus Cisplatin in Patients With Locally Advanced or Metastatic Urothelial Carcinoma
Phase II, multicenter, non-randomized, single-arm, open-label trial of atezolizumab in combination of split-doses of gemcitabine plus cisplatin in patients with locally advanced or metastatic urothelial carcinoma. The Aurea trial aims to evaluate the preliminary efficacy of atezolizumab plus split-dose gemcitabine and cisplatin (GC) for the first-line setting, in patients with histologically confirmed advanced (locally advanced and metastatic) urothelial cancer in terms of overall response rate (ORR) assessed by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary objectives include: efficacy (clinical benefit rate, duration of response, time to response, overall survival and progression-free survival); safety (frequency and severity of adverse events assessed by NCI CTCAE v5.0) and exploratory endpoints ( correlation of prognostic biomarkers/factors with efficacy and relationship between the expression of PD-L1 and microbiome with ORR and PFS). At least 66 patients will be included. The treatment schedule is as follows: Atezolizumab at a fixed dose of 1200 mg/m2 by intravenous (IV) infusion on D1 of each 21-day cycle up to disease progression, unacceptable toxicity or absence of clinical benefit. Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle plus Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles.
The results of trials combining checkpoint inhibitors or platinum-based chemotherapy plus PD-1/PD-L1 inhibitors are eagerly awaited. The combination of split cisplatin with atezolizumab is a feasible treatment that may provide better outcomes than carboplatin/based combinations. In the IMvigor130, 52% of patients considered cisplatin eligible at the entry of the study were treated with carboplatin. Subanalysis presented at European Society of Medical Oncology (ESMO) 2019 (Grande E, et al. 2019) has also shown a longer median OS are achieved with cisplatin-based chemotherapy combined with atezolizumab (21.7 months) when compared to the carboplatin-based chemotherapy plus atezolizumab (14.2 months), with similar findings when it comes to PFS 8.8 months with cisplatin/gemcitabine/atezolizumab vs 7.1 months carboplatin/gemcitabine/atezolizumab. A reasonable strategy may be the use of split cisplatin with atezolizumab to increase the number of patients receiving cisplatin. The AUREA study is a multicenter, open labelled, single arm, multicohort Phase II clinical trial of of atezolizumab in combination of split-dose cisplatin plus gemcitabine in patients with locally advanced or metastatic urothelial carcinoma (additional details on the eligibility criteria of the study are found in section 6 of this protocol). The design includes screening phase, combined treatment initial phase, monotherapy treatment phase, follow-up phase and translational research with biopsies, blood samples and faecal samples. The dose scheme includes the initial dose of atezolizumab (1200 mg) intravenously administered every 21 days (one cycle) up to disease progression, unacceptable toxicity or absence of clinical benefit. Dose adjustment or dose reductions of atezolizumab are not expected. AUREA is an Investigator Initiated Study, the Sponsor will supply Atezolizumab for up to 24 months of treatment for each patient. For those patients in which the PI considers that the best option for the patient is continuing atezolizumab for more than 24 months, available commercial Site supplies should be used, after managed local administrative regulation. Gemcitabine 1000 mg/m2 IV on D1 and 1000 mg/m2 IV on D8 of each 21-day cycle plus Cisplatin 70 mg/m2 by IV on split-dose schedule of 35 mg/m2 on day 1 (D1) and 35 mg/m2 on day 8 (D8) for up to 6 cycles. Study treatment will begin as soon as possible after signing the informed consent. Before each treatment administration chemotherapy/atezolizumab administration laboratory, medical consulting and other determinations will be performed to ensure that treatment can be safely administered. A CT Scan or MRI will be performed at baseline, on week 9, week 18 and then every 12 weeks (q12w) ± 1w until objective disease progression as per PI's criteria or death (whichever comes first). Blood samples for biomarkers studies should be collected before administration of cycle 4 and at the time of Progression Disease (PD) (end of treatment if applicable). For patients with progression reported as per RECIST criteria at week 9, continuity of treatment with atezolizumab should be evaluated by the PI of each site as per clinical benefit criteria. ;
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