| General information |
| Database: | DB00550 |
| Objective: | To assess the efficacy and tolerability of everolimus in advanced urothelial carcimoma (UC). |
| Authors: | Milowsky MI, et al |
| Title: | Phase II study of everolimus in metastatic urothelial cancer |
| Journal: | BJU Int. |
| Year: | 2013 |
| PMID: | 23551593 |
| Trial Design |
| Clinical Trial Id: | NCT00805129 |
| Agent: | everolimus
|
| Target: | Serine/threonineprotein kinase mTOR
|
| Cancer Type: | Urothelial Carcinoma |
| Cancer Subtype: | advanced urothelial carcinoma |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | Phase II study |
| Key Patients Feature: | Patients with previously treated progressive metastaticUC of the bladder, renal pelvis, ureter or urethra, histologically confirmed at the Memorial SloanKetteringCancer Center, were eligible for the present study.Progressive disease was defined as new or progressingunidimensionally measurable lesions on crosssectionalimaging. Previous therapy included one to four cytotoxicagents administered in the perioperative or metastaticsetting because conventional chemotherapy ranges fromone drug (e.g. gemcitabine) to regimens containing fouragents (e.g. methotrexate, vinblastine, doxorubicin andcisplatin). The previous therapy must have included at leastone of the agents: cisplatin, carboplatin, paclitaxel, docetaxelor gemcitabine. At least 4 weeks must have elapsedsubsequent to radiotherapy or chemotherapy. Pretreatmenttumour tissue was required for mTOR pathway markeranalysis. Additional inclusion criteria included: Karnofskyperformance status 60; age 18 years; total serumbilirubin 1.5; serum aspartate transaminase and serumalanine transaminase 2.5 £¤ upper limit of normal (ULN), or serum aspartate transaminase and serum alaninetransaminase 5 £¤ ULN if liver function abnormalitieswere related to malignancy; absolute neutrophil count 1.5 £¤ 109/L; platelets >100 £¤ 109/L; haemoglobin>9.0 g/dL; creatinine 1.5 £¤ ULN; internationalnormalized ratio <1.3 (or <3 on anticoagulants); fastingserum cholesterol 300 mg/dL; fasting triglycerides 2.5 £¤ ULN |
| Biomarker: | NA |
| Biomark Analysis: | Studies aiming to define the genetic basis of everolimusactivity in individual responders are ongoing |
| Control Group Info: | single arm |
| Treatment Info: | Everolimus was administered orally at 10 mg daily continuously (one cycle = 4 weeks). Therapy was continued until progression of disease (POD) or unacceptable toxicity. |
| Primary End Point: | 2month progression free survival (PFS) and the safety |
| Secondary End Point: | response rate |
| Patients Number: | 45 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | There were two partial responses in nodal metastases, with one patient achieving a 94% decrease in target lesions and remaining on drug at 26 months. An additional 12 patients exhibited minor tumour regression. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | The median (95% CI) PFS for all 45 patients and the 37 evaluable patients was 2.6 (1.8-3.5) months and 3.3 (2.1-3.7) months |
| Median OS A vs. C: | the median (95% CI) OS was 8.3 (5.5-12.1) months and 9.8 (7.8-15.2) months, respectively |
| Adverse Event(agent arm): | Grade 3/4 everolimusrelated toxicities were observed in 29 (64%) patients. A dose reduction was necessary in nine (20%) patients. The most common grade 3/4 toxicities were fatigue, infection, anaemia, lymphopaenia, hyperglycaemia and hypophosphataemia. |
| Conclusions: | Although everolimus did not meet its primary endpoint, one partial response, one nearcomplete response and ttheylve minor regressions were observed. Everolimus possesses meaningful antitumour activity in a subset of patients with advanced UC. Studies aiming to define the genetic basis of everolimus activity in individual responders are ongoing. |