Clinical trial NCT00094497: Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT)
Official title: First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Carcinoma, Adrenal Cortical
Lead sponsor: Collaborative Group for Adrenocortical Carcinoma Treatment
Sponsor class: OTHER
Collaborators: name: German Federal Ministry of Education and Research
name: National Cancer Institute (NCI)
First posted: 2004-10-20
Enrollment: 304
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether treatment with etoposide, doxorubicin, cisplatin and mitotane (EDP/M) prolongs survival as compared to streptozotocin and mitotane (Sz/M) in patients with advanced adrenocortical carcinoma (ACC) whose disease is not amenable to complete surgical resection.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival
timeFrame: every 8 weeks until death up to 5 years
Secondary outcomes:
measure: Progression-free Survival
timeFrame: every 8 weeks until progression or death up to 5 years
measure: Change in Quality of Life as Measured by QLQ-C30
timeFrame: baseline and 8 weeks
measure: Best Overall Response Rate
timeFrame: every 8 weeks up to 5 years
measure: Number of Disease-free Patients
timeFrame: every 8 weeks until progression (up to 5 years)
Other outcomes:
measure: TTP of Both Regimens as Second Line Treatment in Case of Failure of the Other Initial Regime
timeFrame: every 8 weeks until progression or until Dec 2010
measure: Pharmakinetics of Mitotane (Substudy)
timeFrame: 11 time points in the first 12 weeks
measure: Impact of Reaching Mitotane Blood Levels Between 14-20 mg/l in Both Arms on Survival and Overall Response Rate
timeFrame: every 8 weeks until progression or until Dec 2010
Locations:
city: Bethesda
country: United States
facility: National Cancer Institute - Center for Cancer Research
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan, Department of Internal Medicine
state: Michigan
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Graz
country: Austria
facility: University of Graz
city: Lille
country: France
facility: Clinique Marc Linquette
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Hospital de Marseille la timone
city: Paris
country: France
facility: Cochin Hospital
city: Pessac
country: France
facility: Hospital Bordeaux haut leveque
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Berlin
country: Germany
facility: Charité-University, Dept. of Endocrinology; Campus Benjamin Franklin
city: Berlin
country: Germany
facility: Charité-Universitätsmedizin Berlin - Campus Mitte
city: Dresden
country: Germany
facility: Dept. of Medicine III
city: Duesseldorf
country: Germany
facility: University of Duesseldorf, Dept. of Endocrrinology
city: Essen
country: Germany
facility: Zentrum für Innere Medizin - Endokrinologie des Universitätsklinikum Essen
city: Hannover
country: Germany
facility: Endokrinologie Medizinische Hochschule Hannover
city: Magdeburg
country: Germany
facility: Otto-von-Guericke University; Dept. of Endocrinology
city: Mainz
country: Germany
facility: Dept of Medicine I
city: Munich
country: Germany
facility: University of Munich, Dept. of Internal Medicine (Innenstadt)
city: Wuerzburg
country: Germany
facility: University of Wuerzburg - Dept. of Medicine
city: Orbassano
country: Italy
facility: University of Turin, Dept of Internal Medicine
city: Padova
country: Italy
facility: Clinica Endocrinologica, Università di Padova, Azienda Ospedaliera di Padova
city: Amsterdam
country: Netherlands
facility: Vrije Universiteit Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum; Dept. of Endocrinology
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum; Dept. of Internal Medicine
city: Groningen
country: Netherlands
facility: University Hospital Groningen; Dept. of Internal Medine
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Gothenburg
country: Sweden
facility: Department of Oncology, Sahlgrenska University Hospital
city: Linköping
country: Sweden
facility: Department of Oncology, Linköping University Hospital
city: Lund
country: Sweden
facility: Department of Medicine, The Jubileum Institute, Lund University
city: Stockholm
country: Sweden
facility: Dept of Surgery, Karolinska Hospital, Stockholm
city: Uppsala
country: Sweden
facility: Uppsala University Hospital - Dept of Medical Sciences
Study officials:
affiliation: Uppsala University Hospital
name: Britt Skogseid, MD
role: STUDY_CHAIR
affiliation: University of Würzburg
name: Martin Fassnacht, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.