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.

STUDY POPULATION

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:

• stage I-III ACC (according to the ENSAT classification) AND
• Ki67≥10%

SAMPLE SIZE

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).

METHODS

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.

RANDOMIZATION

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:

1. Arm A (cisplatin+etoposide +/- mitotane): in the first 12 weeks after randomization, clinical visits every 3 weeks (±3 days) will include:

   Physical examination Report of side effects and concomitant medications CBC Serum chemistry profile Endocrine assessment Serum mitotane evaluation (if applicable)

2. Arm B (mitotane or observation): in the first 12 weeks after randomization, every 4 weeks, clinical visits will include:

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.

Inclusion Criteria:

• Histologically confirmed diagnosis of ACC (Weiss score of ≥ 3); all tumor specimens can be reviewed a posteriori by a reference pathologis
• High risk of relapse within 60 days of surgical resection of primary tumor with curative intent with either microscopically complete resection (R0, microscopically positive margins (R1), or undetermined margins (RX, based on surgical or pathological reports without unequivocal evidence of metastasis in the perioperative imaging).
• Ki67≥10% (to be determined by an experienced pathologist in each participating center and preferably via quantitative imaging analysis).
• Have perioperative imaging (CT with contrast or MRI of the chest/abdomen/pelvis) demonstrating no unequivocal evidence of disease within 4 weeks before randomization. Patients with indeterminate non-specific nodules (<1 cm for soft tissue lesions and <1.5 cm in the short dimension for lymph nodes) will be permitted to participate in this study.
• Be 18 years old or older.
• Have a negative pregnancy test no more than 7 days before starting treatment
• Adequate contraception
• Have an Eastern Cooperative Oncology Group performance status 0.2
• Have an adequate bone marrow reserve (neutrophils >1,000/mm3 and/or platelets >80,000/mm3)
• Have an adequate organ function (including renal, liver and cardiac function)
• Be able to comply with the protocol procedures and provide written informed consent.

Exclusion Criteria:

• The time between primary surgery and randomization is >60 days
• They have undergone repeated surgery for recurrence of disease
• They have a history of recent or active prior malignancy, except for cured non-melanoma skin cancer, cured in situ cervical carcinoma, breast ductal carcinoma in situ, or other treated malignancies where there has been no evidence of disease for at least 2 years
• They have renal insufficiency (estimated glomerular filtration rate [GFR] <50 mL/min/1.73 m2) or significant liver insufficiency (serum bilirubin>2 times the upper normal range and/or serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST]>3 times the upper normal range). GFRs will be calculated according to the validated formula (MDRD)
• They are pregnant or breast feeding
• They have congestive heart failure (ejection fraction<45%). In patients with a history of cardiac disease, a baseline two-dimensional echocardiogram is needed to document ejection fraction. In patients without prior cardiac disease, a baseline electrocardiogram (EKG) is sufficient if there is no evidence of acute ischemic changes or prior evidence of myocardial infarction. If EKG results are abnormal (ischemic changes, significant arrhythmia, or suggestion of prior myocardial infarction), a two-dimensional echocardiogram will be obtained to assess ejection fraction
• They have preexisting grade 2 peripheral neuropathy
• They underwent previous or current treatment with mitotane or other antineoplastic drugs for ACC
• They underwent previous radiotherapy for ACC
• They have any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration or that, in the judgment of the investigator, would make the patient inappropriate for entry into this study.