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

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.

• Etoposide (Drug)
• Doxorubicin (Drug)
• Cisplatin (Drug)
• Streptozotocin (Drug)
• Mitotane (Drug)

Primary outcomes

• Overall Survival [every 8 weeks until death up to 5 years]: participants who died among those randomized to first-line therapy

Secondary outcomes

• Progression-free Survival [every 8 weeks until progression or death up to 5 years]
• Change in Quality of Life as Measured by QLQ-C30 [baseline and 8 weeks]: scale ranged from 0 to 100 with higher score meaning greater quality of life
• Best Overall Response Rate [every 8 weeks up to 5 years]: RECIST 1.0 was used to evaluate response
• Number of Disease-free Patients [every 8 weeks until progression (up to 5 years)]: complete response or disease-free by time of surgery

Other outcomes

• TTP of Both Regimens as Second Line Treatment in Case of Failure of the Other Initial Regime [every 8 weeks until progression or until Dec 2010]
• Pharmakinetics of Mitotane (Substudy) [11 time points in the first 12 weeks]: 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).
• Impact of Reaching Mitotane Blood Levels Between 14-20 mg/l in Both Arms on Survival and Overall Response Rate [every 8 weeks until progression or until Dec 2010]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologically confirmed diagnosis of adrenocortical carcinoma
* Locally advanced or metastatic disease not amenable to radical surgery resection (Stage III-IV)
* Radiologically monitorable disease
* ECOG performance status 0-2
* Life expectancy > 3 months
* Age ≥18 years
* Adequate bone marrow reserve (neutrophils > 1500/mm3 and platelets > 100,000/mm3)
* Effective contraception in pre-menopausal female and male patients
* Patient's written informed consent
* Ability to comply with the protocol procedures (including availability for follow-up visits)
* Previous palliative surgery, radiotherapy or radiofrequency ablation is acceptable as long as radiologically monitorable disease is verifiable afterwards.

Exclusion Criteria:

* History of prior malignancy, except for cured non-melanoma skin cancer, curatively in situ cervical carcinoma, or other cancers treated with no evidence of disease for at least five years.
* Previous cytotoxic chemotherapy for adrenocortical carcinoma
* Renal insufficiency (serum creatinine ≥2 mg/dl or creatinine clearance ≤ 50 ml/min)
* Hepatic insufficiency (serum bilirubin ≥2 x the institutional upper limit of normal range and/or serum transaminases ≥ 3 x the institutional upper limit of normal range; exception: in patients on mitotane, transaminase levels up to 5 x the institutional upper limit of normal range are acceptable)
* Pregnancy or breast feeding
* Known hypersensitivity to any drug included in the treatment protocol
* Presence of active infection
* Any other severe clinical condition that in the judgment of the local investigator would place the patient at undue risk or interfere with the study completion
* Decompensated heart failure (ejection fraction <50%), myocardial infarction or revascularization procedure during the last 6 months, unstable angina pectoris, and uncontrolled cardiac arrhythmia
* Current treatment with other experimental drugs and/or previous participation in clinical trials with other experimental agents for adrenocortical carcinoma
* Prisoners

Participant flow

Outcome results

• Overall Survival (Primary), Number, participants: EDP-M 108; Sz-M 124
• Progression-free Survival (Secondary), Median, months: EDP-M 5.0 (3.5 to 6.9); Sz-M 2.1 (2.04 to 2.33)
• Change in Quality of Life as Measured by QLQ-C30 (Secondary), Mean, units on a scale: EDP-M -6.0 +/- 21.4; Sz-M -7.7 +/- 25.6
• Best Overall Response Rate (Secondary), Number, participants: EDP-M 2; Sz-M 1
• Number of Disease-free Patients (Secondary), Number, participants: EDP-M 6; Sz-M 3
• TTP of Both Regimens as Second Line Treatment in Case of Failure of the Other Initial Regime (Other pre specified)
• Pharmakinetics of Mitotane (Substudy) (Other pre specified)
• Impact of Reaching Mitotane Blood Levels Between 14-20 mg/l in Both Arms on Survival and Overall Response Rate (Other pre specified)

Adverse events

Time frame: up to 5 years

Serious adverse events by term

• Results publication: Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardiere C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Muller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. doi: 10.1056/NEJMoa1200966. Epub 2012 May 2. PMID 22551107

• Britt Skogseid, MD, Study chair, Uppsala University Hospital
• Martin Fassnacht, MD, Principal investigator, University of Würzburg