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

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ClinicalTrials.gov Identifier: NCT00094497
Recruitment Status : Completed
First Posted : October 20, 2004
Results First Posted : September 21, 2016
Last Update Posted : September 21, 2016
German Federal Ministry of Education and Research
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Martin Fassnacht, Collaborative Group for Adrenocortical Carcinoma 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.

Condition or disease Intervention/treatment Phase
Carcinoma, Adrenal Cortical Drug: Etoposide Drug: Doxorubicin Drug: Cisplatin Drug: Streptozotocin Drug: Mitotane Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 304 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment
Study Start Date : June 2004
Actual Primary Completion Date : December 2010
Actual Study Completion Date : December 2010

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: EDP-M
etopodide, doxorubicin, cisplatin and mitotane
Drug: Etoposide
Drug: Doxorubicin
Drug: Cisplatin
Drug: Mitotane
Active Comparator: Sz-M
streptozotocin and mitotane
Drug: Streptozotocin
Drug: Mitotane

Primary Outcome Measures :
  1. Overall Survival [ Time Frame: every 8 weeks until death up to 5 years ]
    participants who died among those randomized to first-line therapy

Secondary Outcome Measures :
  1. Progression-free Survival [ Time Frame: every 8 weeks until progression or death up to 5 years ]
  2. Change in Quality of Life as Measured by QLQ-C30 [ Time Frame: baseline and 8 weeks ]
    scale ranged from 0 to 100 with higher score meaning greater quality of life

  3. Best Overall Response Rate [ Time Frame: every 8 weeks up to 5 years ]
    RECIST 1.0 was used to evaluate response

  4. Number of Disease-free Patients [ Time Frame: every 8 weeks until progression (up to 5 years) ]
    complete response or disease-free by time of surgery

Other Outcome Measures:
  1. 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 ]
  2. Pharmakinetics of Mitotane (Substudy) [ Time Frame: 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).

  3. 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 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00094497

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Sponsors and Collaborators
Collaborative Group for Adrenocortical Carcinoma Treatment
German Federal Ministry of Education and Research
National Cancer Institute (NCI)
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Study Chair: Britt Skogseid, MD Uppsala University Hospital
Principal Investigator: Martin Fassnacht, MD University of Würzburg
Additional Information:
Publications of Results:
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Responsible Party: Martin Fassnacht, Co-PI, Collaborative Group for Adrenocortical Carcinoma Treatment
ClinicalTrials.gov Identifier: NCT00094497    
Obsolete Identifiers: NCT00924144
Other Study ID Numbers: CO-ACT-001
First Posted: October 20, 2004    Key Record Dates
Results First Posted: September 21, 2016
Last Update Posted: September 21, 2016
Last Verified: September 2016
Additional relevant MeSH terms:
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Adrenocortical Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Adrenal Cortex Neoplasms
Adrenal Gland Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Adrenal Cortex Diseases
Adrenal Gland Diseases
Endocrine System Diseases
Antineoplastic Agents
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Antineoplastic Agents, Hormonal