Carcinoma, Adrenal Cortical
Conditions
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.
Interventions
Sponsors
German Federal Ministry of Education and Research
National Cancer Institute (NCI)
Collaborative Group for Adrenocortical Carcinoma Treatment
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | every 8 weeks until death up to 5 years | participants who died among those randomized to first-line therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Progression-free Survival | every 8 weeks until progression or death up to 5 years | — |
| Best Overall Response Rate | every 8 weeks up to 5 years | RECIST 1.0 was used to evaluate response |
| Number of Disease-free Patients | every 8 weeks until progression (up to 5 years) | complete response or disease-free by time of surgery |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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). |
| 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 | — |
Countries
Australia, Austria, France, Germany, Italy, Netherlands, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| EDP-M etopodide, doxorubicin, cisplatin and mitotane
Etoposide
Doxorubicin
Cisplatin
Mitotane
participants who progressed during first line therapy, were eligible to the alternative treatment (Sz-M) | 151 |
| Sz-M streptozotocin and mitotane
Streptozotocin
Mitotane
participants who progressed during first line therapy, were eligible to the alternative treatment (EDP-M) | 153 |
| Total | 304 |
Baseline characteristics
| Characteristic | EDP-M | Sz-M | Total |
|---|---|---|---|
| Age, Customized >= 18 years | 151 participants | 153 participants | 304 participants |
| ECOG 0 | 73 participants | 72 participants | 145 participants |
| ECOG 1 | 64 participants | 60 participants | 124 participants |
| ECOG 2 | 13 participants | 21 participants | 34 participants |
| ECOG 4 | 1 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 91 Participants | 92 Participants | 183 Participants |
| Sex: Female, Male Male | 60 Participants | 61 Participants | 121 Participants |
| tumor stage III | 0 participants | 1 participants | 1 participants |
| tumor stage IV | 151 participants | 152 participants | 303 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 86 / 148 | 62 / 149 |
Outcome results
Primary
Overall Survival
participants who died among those randomized to first-line therapy
Time frame: every 8 weeks until death up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EDP-M | Overall Survival | 108 participants |
| Sz-M | Overall Survival | 124 participants |
Secondary
Best Overall Response Rate
RECIST 1.0 was used to evaluate response
Time frame: every 8 weeks up to 5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| EDP-M | Best Overall Response Rate | disease-free by time of surgery | 4 participants |
| EDP-M | Best Overall Response Rate | progressive disease | 43 participants |
| EDP-M | Best Overall Response Rate | partial response | 29 participants |
| EDP-M | Best Overall Response Rate | did not receive treatment | 3 participants |
| EDP-M | Best Overall Response Rate | complete response | 2 participants |
| EDP-M | Best Overall Response Rate | could not be evaluated | 17 participants |
| EDP-M | Best Overall Response Rate | stable disease | 53 participants |
| Sz-M | Best Overall Response Rate | could not be evaluated | 13 participants |
| Sz-M | Best Overall Response Rate | complete response | 1 participants |
| Sz-M | Best Overall Response Rate | partial response | 11 participants |
| Sz-M | Best Overall Response Rate | stable disease | 34 participants |
| Sz-M | Best Overall Response Rate | progressive disease | 88 participants |
| Sz-M | Best Overall Response Rate | did not receive treatment | 4 participants |
| Sz-M | Best Overall Response Rate | disease-free by time of surgery | 2 participants |
Secondary
Change in Quality of Life as Measured by QLQ-C30
scale ranged from 0 to 100 with higher score meaning greater quality of life
Time frame: baseline and 8 weeks
Population: participants with data on both time points
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-M | Change in Quality of Life as Measured by QLQ-C30 | -6.0 units on a scale | Standard Deviation 21.4 |
| Sz-M | Change in Quality of Life as Measured by QLQ-C30 | -7.7 units on a scale | Standard Deviation 25.6 |
Secondary
Number of Disease-free Patients
complete response or disease-free by time of surgery
Time frame: every 8 weeks until progression (up to 5 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EDP-M | Number of Disease-free Patients | 6 participants |
| Sz-M | Number of Disease-free Patients | 3 participants |
Secondary
Progression-free Survival
Time frame: every 8 weeks until progression or death up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EDP-M | Progression-free Survival | 5.0 months |
| Sz-M | Progression-free Survival | 2.1 months |
Other Pre-specified
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
Other Pre-specified
Pharmakinetics of Mitotane (Substudy)
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
Other Pre-specified
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