Adjuvant Chemotherapy vs. Observation/Mitotane After Primary Surgical Resection of Localized Adrenocortical CarcInoma (ACACIA)
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|ClinicalTrials.gov Identifier: NCT03723941|
Recruitment Status : Recruiting
First Posted : October 30, 2018
Last Update Posted : October 30, 2018
|First Submitted Date ICMJE||October 9, 2018|
|First Posted Date ICMJE||October 30, 2018|
|Last Update Posted Date||October 30, 2018|
|Actual Study Start Date ICMJE||July 1, 2018|
|Estimated Primary Completion Date||June 30, 2020 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Comparison of the recurrence-free survival (RFS) status in patientis treated with adiuvant chemotherapy with or without mitotane (arm A) versus no treatment or adjuvant mitotane (arm B). [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months ]
Evaluation of recurrence-free survival (RFS). Recurrence will be objectively assessed every 16 weeks by imaging the chest/abdomen/pelvis by either computed tomography (CT; with slice thickness of 5 mm or less) or magnetic resonance imaging (MRI). Suspected lesions will be accurately measured in at least one dimension (the longest diameter in the plane of measurement will be recorded). Soft tissue lesions must have a minimum size of 10 mm, and suspected malignant lymph nodes must be more than 15 mm (short axis) to be considered pathological.
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||No Changes Posted|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures
||BioBank [ Time Frame: Baseline ]
Available tissue specimens (formalin-fixed paraffin-embedded or frozen tissues) plus one sample of serum, plasma and urine, will be collected before randomization for each patient enrolled in this study.
|Original Other Pre-specified Outcome Measures||Same as current|
|Brief Title ICMJE||Adjuvant Chemotherapy vs. Observation/Mitotane After Primary Surgical Resection of Localized Adrenocortical CarcInoma|
|Official Title ICMJE||Mitotane With or Without Cisplatin and Etoposide After Surgery in Treating Participants With Stage I-III Adrenocortical Cancer With High Risk of Recurrence|
|Brief Summary||Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Despite complete resection of early-stage disease recurrence rates in ACC are very high (60%.70%). Patients with Ki67 ≥ 10% are considered at high risk for ACC recurrence, whereas patients with Ki67<10% are considered to have low/intermediate risk for recurrence. No study are ongoing on adjuvant systemic therapy in ACC patients that are at high risk of relapse. These patients represent 70-80% of all ACC radically operated. In this setting mitotane is widely prescribed. The efficacy of mitotane is known to be dependent on the attainment of serum drug levels in the so called therapeutic range that is above 14 mg/l. However, ACC patients with high relapse risk may develop disease recurrence before mitotane serum levels attain the target concentration. Chemotherapy with cisplatin containing regimen was shown to be efficacious in the management of ACC in few phase II trials. Based on the background, there is a strong rationale of administering chemotherapy in radically operated ACC patients with high risk of relapse defined as follows: stage I-III ACC (according to the ENSAT classification) with either microscopically complete resection (R0), microscopically positive margins (R1), or undetermined margins (RX) and Ki67≥10% (for a further definition of this condition, see the study population paragraph). In clinical practice, adjuvant mitotane alone or cisplatin-based chemotherapy or the combination of both are used worldwide in patients at high risk of relapse, but there is no prospective validation of these treatments. The investigators will test the efficacy of the combination of cisplatin plus etoposide (plus/minus mitotane according to the investigator preference) in comparison with the actual best routine practice consisting of mitotane or no therapy (according to the personal belief of clinical investigator). This study is parto of the international trial registry ADIUVO-2 coordinated by MD Anderson Center of Huston (Texas).|
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an annual rate of 0.5.2 cases per million population. Despite complete resection of early-stage disease recurrence rates in ACC are very high (60%.70%). Patients with Ki67 ≥ 10% are considered at high risk for ACC recurrence, whereas patients with Ki67<10% are considered to have low/intermediate risk for recurrence. Due to rarity of the disease no data from randomized clinical trials are available on the efficacy of any adjuvant therapies. Mitotane has been widely used in the adjuvant setting in ACC on the basis of the findings of a retrospective multicenter report in which relapse free survival (RFS) was significantly prolonged in patients treated with adjuvant mitotane compared with two control groups who were not given mitotane. The retrospective design of this study resulted in controversy about the benefit of adjuvant mitotane and led to a prospective clinical trial to compare mitotane to placebo as adjuvant therapy in low-risk/intermediate-risk ACC patients who have low Ki67 expression (<10%; ADIUVO study, ClinicalTrials.gov Identifier: NCT00777244).
No study are ongoing on adjuvant systemic therapy in ACC patients that are at high risk of relapse. These patients represent 70-80% of all ACC radically operated. In this setting mitotane is widely prescribed. The efficacy of mitotane is known to be dependent on the attainment of serum drug levels in the so called therapeutic range that is above 14 mg/l. These mitotane levels should be maintained over time. The results of a recent retrospective analysis on the impact of serum mitotane levels on prognosis in 122 ACC patients, who were radically resected, showed that the 63 patients who reached and maintained the target mitotane concentrations during follow-up had a significantly lower rate of recurrence than the 59 patients who failed to keep mitotane levels as high. However, the attainment of therapeutic range of mitotane usually require 2-3 months whatever is the schedule adopted. ACC patients with high relapse risk may develop disease recurrence before mitotane serum levels attain the target concentration.
Chemotherapy with cisplatin containing regimen was shown to be efficacious in the management of ACC in few phase II trials.
The results of the only phase III trial conducted up to now, the FIRM-ACT study, found that mitotane combined with cisplatin-based chemotherapy was superior to mitotane combined with streptozocin in terms of progression free survival and overall survival in patients with advanced/metastatic ACC. The cytotoxic activity of chemotherapy is rapid and this is the rationale of administering a cisplatin containing regimen in adjuvant setting of ACC patients with high risk of disease relapse.
Adjuvant mitotane treatment improved RFS and overall survival (OS) in a retrospective study, and adjuvant mitotane is undergoing prospective evaluation in low-risk/intermediate-risk ACC patients (Ki67<10%; ADIUVO study). However, Mitotane alone could be not adequate as adjuvant therapy in highly proliferating ACC since the drug efficacy is strictly dependent on the attainment of circulating concentration levels >14 mg/l that is usually achieved after 2-3 months of therapy. In this lead time disease recurrence may occur.
Based on the background, there is a strong rationale of administering chemotherapy in radically operated ACC patients with high risk of relapse defined as follows: stage I-III ACC (according to the ENSAT classification) with either microscopically complete resection (R0), microscopically positive margins (R1), or undetermined margins (RX) and Ki67≥10% (for a further definition of this condition, see the study population paragraph). In clinical practice, adjuvant mitotane alone or cisplatin-based chemotherapy or the combination of both are used worldwide in patients at high risk of relapse, but there is no prospective validation of these treatments.
In this multicenter prospective randomized clinical study, that will test the efficacy of the combination of cisplatin plus etoposide (plus/minus mitotane according to the investigator preference) in comparison with the actual best routine practice consisting of mitotane or no therapy (according to the personal belief of clinical investigator). This proposed randomized prospective study is needed to assess the efficacy and safety of chemotherapy with a cisplatin regimen in high-risk ACC patients after initial surgical resection. There are no studies ongoing testing any adjuvant therapies in radically operated ACC with high risk of relapse and death.
STUDY DESIGN AND DURATION
The study is designed as a prospective, randomized, open-label, stratified, nation-based multi-center, phase III trial for patients with ACC and Ki67≥10% after resection with curative intent.
Patients will be stratified on the basis of the European Network for the Study of Adrenal Tumors (ENSAT) stage (I/II vs. III) and whether the clinical investigator decide to administer mitotane or not.
The evaluation of ACC recurrence with imaging techniques (TC scan or MR) will be performed every 4 months for the first 2 years and then every 6 months till the 4th year.
In this study, the planned patient enrollment time is two years and the follow-up time is one year.
An international large scale prospective randomized clinical trial with a similar design of the present study is currently being submitted to national and international calls for funds. If this trial will be funded and will start, the present trial will converge to the international one, and the funds obtained by AIFA wil be employed to manage the italian part.
The patients that will be enrolled in this study will have newly diagnosed and radically operated ACC at high risk of disease recurrence defined as follows:
The sample size calculation is performed on the basis of the following assumption. The median RFS for the mitotane group with Ki67≥10% is estimated to be 20 months. It is assume that Cisplatin + Etoposide therapy can reduce the risk of disease recurrence or death assuming a median RFS of 34 months for arm A, which translates into a hazard ratio (Cisplatin + Etoposide [+/- mitotane] vs. observation [+/- mitotane] of 0.59, and a drop-off rate of 5% in each arm. Therefore, a total sample size of 198 patients (rounded to 200, 100 in each arm) is needed to achieve a power of 80% to detect an improvement in median RFS of 14-months (from 20 months to 34), with a one-sided significance level of 0.05 and an interim analysis when 1/3 of events will be recorded. The study duration is expected to be about 3 years: 2-years for recruitment and 1-year of minimum follow-up. The Clinical Epidemiology Unit - Clinical Trial Center of the Città della Salute e della University Hospital in Turin, will provide a web based procedure for randomization and a dedicated database for eCRF (www.epiclin.it).
Etoposide 100 mg/m2 will be administered IV on days 1, 2, 3 diluted in 500 mL of isotonic NaCl or 5% dextrose over 60 minutes.
Cisplatin, 80 mg/m2 will be administered IV on day 1, diluted in 500 mL of isotonic NaCl, over 60 minutes. Before cisplatin, 1000 ml isotonic NaCl with addition of 20 mmol potassium is given during 2 h. Cisplatin infusion is administered over 60 minutes. Cisplatin administration is followed by 1000 ml isotonic NaCl with addition of 5 mmol Magnesium and 20 mmol potassium during 1 hour. 500 mL mannitol IV can also be administered at a concentration of 150 mg/mL during 1 hour according to the inestigator routine clinical practice. Injections of small doses of diuretics (e.g. furosemide 10-20 mg) should be given IV to ensure diuresis and avoid retention of fluids.
Cisplatin and etoposide regimen will be administered every 21 days for 4 cycles.
Treatment should start within 7 days from randomization. If the clinical investigator decide to prescribe mitotane (alone or in combination with chemotherapy according to the randomization treatment arm), the drug will be administered orally to reach a plasma level of 14.20 mg/L (or the maximum tolerated dose if unable to reach therapeutic levels). The mitotane dosage scheme is the responsibility of the local investigator, but an initial dose of 3.6 g daily is usually prescribed to reach therapeutic plasma mitotane levels (14.20 mg/L). Dosage will be further adjusted according to blood concentrations and clinical assessment.
Analysis of serum mitotane levels will be performed monthly by a reputable clinical laboratory chosen by each center to reflect clinical practice patterns. All patients on mitotane will receive concomitant glucocorticoid replacement therapy with the option of using plasma adrenocorticotropic hormone levels to guide steroid replacement.
Mitotane will be administered to the two study arms until ACC relapse, intolerable toxicity, or for a total period of 2 years.
The randomization procedure will be performed online and implemented with the electronic case report form at the web-site www.epiclin.cpo.it.
The procedure will be stratified on the following factors:
Mitotane use Disease stage (I/II vs. III) Ki67 percentage (10%.20% vs. >20%)
SCHEDULED VISITS AND PROCEDURES
The baseline evaluation (1 week before randomization) includes:
History and physical examination Concomitant medications Surgical and pathological reports Complete blood count Serum biochemistry profile, lipid profile Endocrine assessment: serum cortisol, testosterone (in women), 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, aldosterone, estradiol (in men and postmenopausal women), adrenocorticotropic hormone (ACTH), plasma renin activity, free T4, and TSH Pregnancy test in women of childbearing potential every 3 months or if there is suspicion for pregnancy EKG CT with contrast (or MRI) of the chest/abdomen/pelvis performed no more than 4 weeks before randomization Written informed consent After the completion of baseline procedures, the patient will be randomized.
The subsequent visits will be as follows:
Physical examination Report of concomitant medications If the patient is receiving mitotane the following data will be requested Report of side effects CBC Serum chemistry profile Endocrine assessment Serum mitotane measurement At 16 weeks (in both study arms), and every 16 weeks until ACC recurrence cross-sectional imaging studies (MRI or CT with contrast medium) of the chest/abdomen/pelvis will be performed. Further imaging can be ordered if deemed necessary by the local investigator (CT or MRI of the brain or bone assessment).
After the first 12 weeks (in both study arms) until ACC recurrence: Every 12 weeks, the clinical visit will include:
Physical examination Report of concomitant medications and side effects CBC Serum chemistry profile Endocrine assessment.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Prospective, randomized, open-label, stratified, nation-based multi-center, phase III trial for patients with ACC and Ki67≥10% after resection with curative intentMasking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Adrenocortical Carcinoma|
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Recruiting|
|Estimated Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Estimated Study Completion Date ICMJE||June 30, 2021|
|Estimated Primary Completion Date||June 30, 2020 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Listed Location Countries ICMJE||Italy|
|Removed Location Countries|
|NCT Number ICMJE||NCT03723941|
|Other Study ID Numbers ICMJE||ACACIA
ADIUVO-2 ( Other Identifier: MD Anderson )
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Alfredo Berruti, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia|
|Study Sponsor ICMJE||Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia|
|Collaborators ICMJE||Not Provided|
|PRS Account||Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia|
|Verification Date||October 2018|
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