Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT)

• Overall survival [ Time Frame: At the final analysis ] [ Designated as safety issue: No ]
  

• Time to progression (TTP) [ Time Frame: At each evaluation (every 8 weeks) ] [ Designated as safety issue: No ]
  
• Quality of life as measured by QLQ-C30 [ Time Frame: at each evaluation ] [ Designated as safety issue: Yes ]
  
• Best overall response rate and duration of response [ Time Frame: At each evaluation (every 8 weeks) ] [ Designated as safety issue: No ]
  
• Number of disease-free patients [ Designated as safety issue: No ]
  
• Impact of reaching mitotane blood levels between 14-20 mg/l in both arms on survival and overall response rate [ Designated as safety issue: No ]
  
• TTP of both regimens as second line treatment in case of failure of the other initial regime [ Designated as safety issue: No ]
  
• Pharmakinetics of mitotane (substudy) [ Time Frame: 11 time points in the first 12 weeks ] [ Designated as safety issue: No ]
  To study the relationship between mitotane dose (daily and cumulative) and mitotane plasma concentrations using one of two pre-defined treatment regimens (high-dose and low-dose).
  
  

The Firm-ACT trial is the first ever conducted randomized controlled phase III trial in adrenocortical carcinoma (ACC), a rare malignancy with poor prognosis. It will provide results leading to the establishment of an urgently needed gold standard chemotherapy regimen for patients with locally advanced or metastatic ACC. To this end the trial compares the two most promising drug combinations investigated in phase II trials, considered by the "International Consensus Conference on Adrenal Cancer" (Ann Arbor/USA, 2003) as valuable first line treatments for advanced ACC. The first regimen consists of etoposide, doxorubicin, cisplatin plus mitotane (EDP-M), the second regiment employs streptozotocin plus mitotane (Sz-M). Over a period of five years this international trial will include 300 patients with advanced ACC from different European countries. Blood mitotane concentrations will be monitored, aiming at drug levels between 14 - 20 mg/L. Patients not responding to the first line treatment will be switched to the alternative regimen. The primary objective of this trial is to investigate whether EDP-M given as first line treatment will prolong survival as compared to Sz-M. Secondary endpoints are quality of life, time to progression, best overall response rate and duration of response. In addition, the trial evaluates the role of reaching therapeutic mitotane serum concentrations for survival and tumour response and assesses the value of the two alternative treatment regimens as second line therapy in advanced ACC. Moreover, the FIRM-ACT trial will generate a lasting structural basis for successful future trials in ACC.

In a substudy of 40 patients a detailed analysis of the pharmacokinetics of oral mitotane will be analysed. Two different mitotane treatment regimens ("low dose" vs. "high dose") will be compared.