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

September 19, 2016 updated by: Martin Fassnacht, Collaborative Group for Adrenocortical Carcinoma Treatment

First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Actual)

304

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Adelaide, Australia, SA 5000
        • Royal Adelaide Hospital
      • Graz, Austria, 8036
        • University of Graz
      • Lille, France
        • Clinique Marc Linquette
      • Lyon, France
        • Centre Léon Berard
      • Marseille, France, 13385
        • Hospital de Marseille la timone
      • Paris, France, 75679
        • Cochin Hospital
      • Pessac, France, 33600
        • Hospital Bordeaux haut leveque
      • Villejuif, France, 94805
        • Institut Gustave Roussy
      • Berlin, Germany
        • Charité-University, Dept. of Endocrinology; Campus Benjamin Franklin
      • Berlin, Germany
        • Charité-Universitätsmedizin Berlin - Campus Mitte
      • Dresden, Germany
        • Dept. of Medicine III
      • Duesseldorf, Germany, 40001
        • University of Duesseldorf, Dept. of Endocrrinology
      • Essen, Germany
        • Zentrum für Innere Medizin - Endokrinologie des Universitätsklinikum Essen
      • Hannover, Germany
        • Endokrinologie Medizinische Hochschule Hannover
      • Magdeburg, Germany, 39120
        • Otto-von-Guericke University; Dept. of Endocrinology
      • Mainz, Germany
        • Dept of Medicine I
      • Munich, Germany, 80336
        • University of Munich, Dept. of Internal Medicine (Innenstadt)
      • Wuerzburg, Germany, 97080
        • University of Wuerzburg - Dept. of Medicine
      • Orbassano, Italy, 10043
        • University of Turin, Dept of Internal Medicine
      • Padova, Italy
        • Clinica Endocrinologica, Università di Padova, Azienda Ospedaliera di Padova
      • Amsterdam, Netherlands, 1007
        • Vrije Universiteit Medisch Centrum
      • Amsterdam, Netherlands, 1105 AZ
        • Academisch Medisch Centrum; Dept. of Endocrinology
      • Eindhoven, Netherlands, 5631 BM
        • Maxima Medisch Centrum; Dept. of Internal Medicine
      • Groningen, Netherlands, 9700
        • University Hospital Groningen; Dept. of Internal Medine
      • Leiden, Netherlands
        • Leiden University Medical Center
      • Gothenburg, Sweden
        • Department of Oncology, Sahlgrenska University Hospital
      • Linköping, Sweden
        • Department of Oncology, Linköping University Hospital
      • Lund, Sweden
        • Department of Medicine, The Jubileum Institute, Lund University
      • Stockholm, Sweden
        • Dept of Surgery, Karolinska Hospital, Stockholm
      • Uppsala, Sweden, 751 85
        • Uppsala University Hospital - Dept of Medical Sciences
    • Maryland
      • Bethesda, Maryland, United States
        • National Cancer Institute - Center for Cancer Research
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan, Department of Internal Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: EDP-M
etopodide, doxorubicin, cisplatin and mitotane
Active Comparator: Sz-M
streptozotocin and mitotane

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival
Time Frame: every 8 weeks until death up to 5 years
participants who died among those randomized to first-line therapy
every 8 weeks until death up to 5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free Survival
Time Frame: every 8 weeks until progression or death up to 5 years
every 8 weeks until progression or death up to 5 years
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
baseline and 8 weeks
Best Overall Response Rate
Time Frame: every 8 weeks up to 5 years
RECIST 1.0 was used to evaluate response
every 8 weeks up to 5 years
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
every 8 weeks until progression (up to 5 years)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
every 8 weeks until progression or until Dec 2010
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).
11 time points in the first 12 weeks
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
every 8 weeks until progression or until Dec 2010

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Chair: Britt Skogseid, MD, Uppsala University Hospital
  • Principal Investigator: Martin Fassnacht, MD, University of Würzburg

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2004

Primary Completion (Actual)

December 1, 2010

Study Completion (Actual)

December 1, 2010

Study Registration Dates

First Submitted

October 19, 2004

First Submitted That Met QC Criteria

October 19, 2004

First Posted (Estimate)

October 20, 2004

Study Record Updates

Last Update Posted (Estimate)

September 21, 2016

Last Update Submitted That Met QC Criteria

September 19, 2016

Last Verified

September 1, 2016

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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