Back to resultsTrial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT)
Primary Purpose
Carcinoma, Adrenal Cortical
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Etoposide
Doxorubicin
Cisplatin
Streptozotocin
Mitotane
Sponsored by
About this trial
This is an interventional treatment trial for Carcinoma, Adrenal Cortical
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
Sites / Locations
- National Cancer Institute - Center for Cancer Research
- University of Michigan, Department of Internal Medicine
- Royal Adelaide Hospital
- University of Graz
- Clinique Marc Linquette
- Centre Leon Berard
- Hospital de Marseille la timone
- Cochin Hospital
- Hospital Bordeaux haut leveque
- Institut Gustave Roussy
- Charité-University, Dept. of Endocrinology; Campus Benjamin Franklin
- Charité-Universitätsmedizin Berlin - Campus Mitte
- Dept. of Medicine III
- University of Duesseldorf, Dept. of Endocrrinology
- Zentrum für Innere Medizin - Endokrinologie des Universitätsklinikum Essen
- Endokrinologie Medizinische Hochschule Hannover
- Otto-von-Guericke University; Dept. of Endocrinology
- Dept of Medicine I
- University of Munich, Dept. of Internal Medicine (Innenstadt)
- University of Wuerzburg - Dept. of Medicine
- University of Turin, Dept of Internal Medicine
- Clinica Endocrinologica, Università di Padova, Azienda Ospedaliera di Padova
- Vrije Universiteit Medisch Centrum
- Academisch Medisch Centrum; Dept. of Endocrinology
- Maxima Medisch Centrum; Dept. of Internal Medicine
- University Hospital Groningen; Dept. of Internal Medine
- Leiden University Medical Center
- Department of Oncology, Sahlgrenska University Hospital
- Department of Oncology, Linköping University Hospital
- Department of Medicine, The Jubileum Institute, Lund University
- Dept of Surgery, Karolinska Hospital, Stockholm
- Uppsala University Hospital - Dept of Medical Sciences
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Active Comparator
Arm Label
EDP-M
Sz-M
Arm Description
etopodide, doxorubicin, cisplatin and mitotane
streptozotocin and mitotane
Outcomes
Primary Outcome Measures
Overall Survival
participants who died among those randomized to first-line therapy
Secondary Outcome Measures
Progression-free Survival
Change in Quality of Life as Measured by QLQ-C30
scale ranged from 0 to 100 with higher score meaning greater quality of life
Best Overall Response Rate
RECIST 1.0 was used to evaluate response
Number of Disease-free Patients
complete response or disease-free by time of surgery
Full Information
NCT ID
NCT00094497
First Posted
October 19, 2004
Last Updated
September 19, 2016
Sponsor
Collaborative Group for Adrenocortical Carcinoma Treatment
Collaborators
German Federal Ministry of Education and Research, National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00094497
Brief Title
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
2. Study Status
Record Verification Date
September 2016
Overall Recruitment Status
Completed
Study Start Date
June 2004 (undefined)
Primary Completion Date
December 2010 (Actual)
Study Completion Date
December 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Collaborative Group for Adrenocortical Carcinoma Treatment
Collaborators
German Federal Ministry of Education and Research, National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carcinoma, Adrenal Cortical
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
304 (Actual)
8. Arms, Groups, and Interventions
Arm Title
EDP-M
Arm Type
Active Comparator
Arm Description
etopodide, doxorubicin, cisplatin and mitotane
Arm Title
Sz-M
Arm Type
Active Comparator
Arm Description
streptozotocin and mitotane
Intervention Type
Drug
Intervention Name(s)
Etoposide
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Intervention Type
Drug
Intervention Name(s)
Streptozotocin
Intervention Type
Drug
Intervention Name(s)
Mitotane
Primary Outcome Measure Information:
Title
Overall Survival
Description
participants who died among those randomized to first-line therapy
Time Frame
every 8 weeks until death up to 5 years
Secondary Outcome Measure Information:
Title
Progression-free Survival
Time Frame
every 8 weeks until progression or death up to 5 years
Title
Change in Quality of Life as Measured by QLQ-C30
Description
scale ranged from 0 to 100 with higher score meaning greater quality of life
Time Frame
baseline and 8 weeks
Title
Best Overall Response Rate
Description
RECIST 1.0 was used to evaluate response
Time Frame
every 8 weeks up to 5 years
Title
Number of Disease-free Patients
Description
complete response or disease-free by time of surgery
Time Frame
every 8 weeks until progression (up to 5 years)
Other Pre-specified Outcome Measures:
Title
TTP of Both Regimens as Second Line Treatment in Case of Failure of the Other Initial Regime
Time Frame
every 8 weeks until progression or until Dec 2010
Title
Pharmakinetics of Mitotane (Substudy)
Description
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).
Time Frame
11 time points in the first 12 weeks
Title
Impact of Reaching Mitotane Blood Levels Between 14-20 mg/l in Both Arms on Survival and Overall Response Rate
Time Frame
every 8 weeks until progression or until Dec 2010
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Britt Skogseid, MD
Organizational Affiliation
Uppsala University Hospital
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Martin Fassnacht, MD
Organizational Affiliation
University of Würzburg
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Cancer Institute - Center for Cancer Research
City
Bethesda
State/Province
Maryland
Country
United States
Facility Name
University of Michigan, Department of Internal Medicine
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Royal Adelaide Hospital
City
Adelaide
ZIP/Postal Code
SA 5000
Country
Australia
Facility Name
University of Graz
City
Graz
ZIP/Postal Code
8036
Country
Austria
Facility Name
Clinique Marc Linquette
City
Lille
Country
France
Facility Name
Centre Leon Berard
City
Lyon
Country
France
Facility Name
Hospital de Marseille la timone
City
Marseille
ZIP/Postal Code
13385
Country
France
Facility Name
Cochin Hospital
City
Paris
ZIP/Postal Code
75679
Country
France
Facility Name
Hospital Bordeaux haut leveque
City
Pessac
ZIP/Postal Code
33600
Country
France
Facility Name
Institut Gustave Roussy
City
Villejuif
ZIP/Postal Code
94805
Country
France
Facility Name
Charité-University, Dept. of Endocrinology; Campus Benjamin Franklin
City
Berlin
Country
Germany
Facility Name
Charité-Universitätsmedizin Berlin - Campus Mitte
City
Berlin
Country
Germany
Facility Name
Dept. of Medicine III
City
Dresden
Country
Germany
Facility Name
University of Duesseldorf, Dept. of Endocrrinology
City
Duesseldorf
ZIP/Postal Code
40001
Country
Germany
Facility Name
Zentrum für Innere Medizin - Endokrinologie des Universitätsklinikum Essen
City
Essen
Country
Germany
Facility Name
Endokrinologie Medizinische Hochschule Hannover
City
Hannover
Country
Germany
Facility Name
Otto-von-Guericke University; Dept. of Endocrinology
City
Magdeburg
ZIP/Postal Code
39120
Country
Germany
Facility Name
Dept of Medicine I
City
Mainz
Country
Germany
Facility Name
University of Munich, Dept. of Internal Medicine (Innenstadt)
City
Munich
ZIP/Postal Code
80336
Country
Germany
Facility Name
University of Wuerzburg - Dept. of Medicine
City
Wuerzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
University of Turin, Dept of Internal Medicine
City
Orbassano
ZIP/Postal Code
10043
Country
Italy
Facility Name
Clinica Endocrinologica, Università di Padova, Azienda Ospedaliera di Padova
City
Padova
Country
Italy
Facility Name
Vrije Universiteit Medisch Centrum
City
Amsterdam
ZIP/Postal Code
1007
Country
Netherlands
Facility Name
Academisch Medisch Centrum; Dept. of Endocrinology
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
Facility Name
Maxima Medisch Centrum; Dept. of Internal Medicine
City
Eindhoven
ZIP/Postal Code
5631 BM
Country
Netherlands
Facility Name
University Hospital Groningen; Dept. of Internal Medine
City
Groningen
ZIP/Postal Code
9700
Country
Netherlands
Facility Name
Leiden University Medical Center
City
Leiden
Country
Netherlands
Facility Name
Department of Oncology, Sahlgrenska University Hospital
City
Gothenburg
Country
Sweden
Facility Name
Department of Oncology, Linköping University Hospital
City
Linköping
Country
Sweden
Facility Name
Department of Medicine, The Jubileum Institute, Lund University
City
Lund
Country
Sweden
Facility Name
Dept of Surgery, Karolinska Hospital, Stockholm
City
Stockholm
Country
Sweden
Facility Name
Uppsala University Hospital - Dept of Medical Sciences
City
Uppsala
ZIP/Postal Code
751 85
Country
Sweden
12. IPD Sharing Statement
Citations:
PubMed Identifier
22551107
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.
Results Reference
result
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Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT)
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