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

• Sponsor: Collaborative Group for Adrenocortical Carcinoma Treatment (Other)
• Overall Status: Completed
• CT.gov ID: NCT00094497
• Collaborator: German Federal Ministry of Education and Research (Other), National Cancer Institute (NCI) (NIH)
• Enrollment: 304
• Locations: 32
• Arms: 2
• Duration (Months): 78
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.1

Study Details

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.

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.

Study Design

• Study Type: Interventional
• 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: Jun 1, 2004
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Overall Survival [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 [every 8 weeks until progression or death up to 5 years]

2. 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

3. Best Overall Response Rate [every 8 weeks up to 5 years]

   RECIST 1.0 was used to evaluate response

4. Number of Disease-free Patients [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 [every 8 weeks until progression or until Dec 2010]

2. 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).

3. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cancer Institute - Center for Cancer Research	Bethesda	Maryland	United States
2	University of Michigan, Department of Internal Medicine	Ann Arbor	Michigan	United States	48109
3	Royal Adelaide Hospital	Adelaide		Australia	SA 5000
4	University of Graz	Graz		Austria	8036
5	Clinique Marc Linquette	Lille		France
6	Centre Leon Berard	Lyon		France
7	Hospital de Marseille la timone	Marseille		France	13385
8	Cochin Hospital	Paris		France	75679
9	Hospital Bordeaux haut leveque	Pessac		France	33600
10	Institut Gustave Roussy	Villejuif		France	94805
11	Charité-University, Dept. of Endocrinology; Campus Benjamin Franklin	Berlin		Germany
12	Charité-Universitätsmedizin Berlin - Campus Mitte	Berlin		Germany
13	Dept. of Medicine III	Dresden		Germany
14	University of Duesseldorf, Dept. of Endocrrinology	Duesseldorf		Germany	40001
15	Zentrum für Innere Medizin - Endokrinologie des Universitätsklinikum Essen	Essen		Germany
16	Endokrinologie Medizinische Hochschule Hannover	Hannover		Germany
17	Otto-von-Guericke University; Dept. of Endocrinology	Magdeburg		Germany	39120
18	Dept of Medicine I	Mainz		Germany
19	University of Munich, Dept. of Internal Medicine (Innenstadt)	Munich		Germany	80336
20	University of Wuerzburg - Dept. of Medicine	Wuerzburg		Germany	97080
21	University of Turin, Dept of Internal Medicine	Orbassano		Italy	10043
22	Clinica Endocrinologica, Università di Padova, Azienda Ospedaliera di Padova	Padova		Italy
23	Vrije Universiteit Medisch Centrum	Amsterdam		Netherlands	1007
24	Academisch Medisch Centrum; Dept. of Endocrinology	Amsterdam		Netherlands	1105 AZ
25	Maxima Medisch Centrum; Dept. of Internal Medicine	Eindhoven		Netherlands	5631 BM
26	University Hospital Groningen; Dept. of Internal Medine	Groningen		Netherlands	9700
27	Leiden University Medical Center	Leiden		Netherlands
28	Department of Oncology, Sahlgrenska University Hospital	Gothenburg		Sweden
29	Department of Oncology, Linköping University Hospital	Linköping		Sweden
30	Department of Medicine, The Jubileum Institute, Lund University	Lund		Sweden
31	Dept of Surgery, Karolinska Hospital, Stockholm	Stockholm		Sweden
32	Uppsala University Hospital - Dept of Medical Sciences	Uppsala		Sweden	751 85

Sponsors and Collaborators

• Collaborative Group for Adrenocortical Carcinoma Treatment
• German Federal Ministry of Education and Research
• National Cancer Institute (NCI)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for more information about this study: First International Randomized trial in locally advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT)

Publications

None provided.

• Responsible Party: Martin Fassnacht, Co-PI, Collaborative Group for Adrenocortical Carcinoma Treatment
• ClinicalTrials.gov Identifier: NCT00094497
• Other Study ID Numbers: CO-ACT-001; NCT00924144
• First Posted: Oct 20, 2004
• Last Update Posted: Sep 21, 2016
• Last Verified: Sep 1, 2016

• Additional relevant MeSH terms: Carcinoma; Adrenocortical Carcinoma; Doxorubicin; Etoposide; Mitotane; Streptozocin

Study Results

Participant Flow

Arm/Group Title	EDP-M	Sz-M
Arm/Group Description	etopodide, doxorubicin, cisplatin and mitotane Etoposide Doxorubicin Cisplatin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (Sz-M)	streptozotocin and mitotane Streptozotocin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (EDP-M)
Period Title: Overall Study
STARTED	151	153
Treated	148	149
Received Second Line Therapy	84	101
COMPLETED	151	153
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	EDP-M	Sz-M	Total
Arm/Group Description	etopodide, doxorubicin, cisplatin and mitotane Etoposide Doxorubicin Cisplatin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (Sz-M)	streptozotocin and mitotane Streptozotocin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (EDP-M)	Total of all reporting groups
Overall Participants	151	153	304
Age, Customized (participants) [Number]
>= 18 years	151 100%	153 100%	304 100%
Sex: Female, Male (Count of Participants)
Female	91 60.3%	92 60.1%	183 60.2%
Male	60 39.7%	61 39.9%	121 39.8%
tumor stage (participants) [Number]
III	0 0%	1 0.7%	1 0.3%
IV	151 100%	152 99.3%	303 99.7%
ECOG (participants) [Number]
0	73 48.3%	72 47.1%	145 47.7%
1	64 42.4%	60 39.2%	124 40.8%
2	13 8.6%	21 13.7%	34 11.2%
4	1 0.7%	0 0%	1 0.3%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EDP-M	Sz-M
Arm/Group Description	etopodide, doxorubicin, cisplatin and mitotane Etoposide Doxorubicin Cisplatin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (Sz-M)	streptozotocin and mitotane Streptozotocin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (EDP-M)
Measure Participants	151	153
Number [participants]	108 71.5%	124 81%

2. Secondary Outcome

Title	Progression-free Survival
Time Frame	every 8 weeks until progression or death up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EDP-M	Sz-M
Arm/Group Description	etopodide, doxorubicin, cisplatin and mitotane Etoposide Doxorubicin Cisplatin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (Sz-M)	streptozotocin and mitotane Streptozotocin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (EDP-M)
Measure Participants	151	153
Median (95% Confidence Interval) [months]	5.0	2.1

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

participants with data on both time points

Arm/Group Title	EDP-M	Sz-M
Arm/Group Description	etopodide, doxorubicin, cisplatin and mitotane Etoposide Doxorubicin Cisplatin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (Sz-M)	streptozotocin and mitotane Streptozotocin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (EDP-M)
Measure Participants	60	39
Mean (Standard Deviation) [units on a scale]	-6.0 (21.4)	-7.7 (25.6)

4. Secondary Outcome

Title	Best Overall Response Rate
Description	RECIST 1.0 was used to evaluate response
Time Frame	every 8 weeks up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EDP-M	Sz-M
Arm/Group Description	etopodide, doxorubicin, cisplatin and mitotane Etoposide Doxorubicin Cisplatin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (Sz-M)	streptozotocin and mitotane Streptozotocin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (EDP-M)
Measure Participants	151	153
complete response	2 1.3%	1 0.7%
disease-free by time of surgery	4 2.6%	2 1.3%
partial response	29 19.2%	11 7.2%
stable disease	53 35.1%	34 22.2%
progressive disease	43 28.5%	88 57.5%
did not receive treatment	3 2%	4 2.6%
could not be evaluated	17 11.3%	13 8.5%

5. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	EDP-M	Sz-M
Arm/Group Description	etopodide, doxorubicin, cisplatin and mitotane Etoposide Doxorubicin Cisplatin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (Sz-M)	streptozotocin and mitotane Streptozotocin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (EDP-M)
Measure Participants	151	153
Number [participants]	6 4%	3 2%

6. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	up to 5 years
Adverse Event Reporting Description	Other non-serious adverse events were not reliably collected and therefore not reported
Arm/Group Title	EDP-M		Sz-M
Arm/Group Description	etopodide, doxorubicin, cisplatin and mitotane Etoposide Doxorubicin Cisplatin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (Sz-M)		streptozotocin and mitotane Streptozotocin Mitotane participants who progressed during first line therapy, were eligible to the alternative treatment (EDP-M)
All Cause Mortality
	EDP-M		Sz-M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	EDP-M		Sz-M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	86/148 (58.1%)		62/149 (41.6%)
Blood and lymphatic system disorders
bone marrow toxicity	17/148 (11.5%)		3/149 (2%)
Endocrine disorders
adrenal insufficiency	5/148 (3.4%)		1/149 (0.7%)
Gastrointestinal disorders
gastrointestinal disorder	6/148 (4.1%)		12/149 (8.1%)
General disorders
fatigue or general health deterioration	8/148 (5.4%)		7/149 (4.7%)
Other	15/148 (10.1%)		13/149 (8.7%)
Hepatobiliary disorders
impaired liver function	0/148 (0%)		7/149 (4.7%)
Infections and infestations
infection	10/148 (6.8%)		4/149 (2.7%)
Nervous system disorders
neurologic toxicity	5/148 (3.4%)		4/149 (2.7%)
Renal and urinary disorders
impaired renal function	1/148 (0.7%)		6/149 (4%)
Respiratory, thoracic and mediastinal disorders
respiratory disorder	9/148 (6.1%)		5/149 (3.4%)
Vascular disorders
cardiovascular or thromboembolic events	10/148 (6.8%)		0/149 (0%)
Other (Not Including Serious) Adverse Events
	EDP-M		Sz-M
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.