Mitotane With or Without Cisplatin and Etoposide After Surgery in Treating Participants With Stage I-III Adrenocortical Cancer With High Risk of Recurrence (ADIUVO-2)

PRIMARY OBJECTIVES:

I. To compare the effect of adjuvant mitotane treatment alone (arm A) with that of adjuvant
mitotane combined with four 21-day cycles of etoposide/cisplatin (arm B) on recurrence-free
survival (RFS) in patients with high-risk adrenocortical carcinoma (ACC) after initial
surgical resection.

SECONDARY OBJECTIVES:

I. Assess overall survival (OS), defined as the time interval between the date of
randomization and the date of death from any cause.

II. Assess the effect of serum mitotane levels, disease stage, and surgical resection margins
on clinical outcomes.

III. Assess the effect of early start (1-6 weeks from surgery) vs. late start (> 6 weeks from
surgery) of adjuvant therapy on clinical outcomes.

IV. Assess serious adverse events (grade 3 and above) according to the National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.03).

V. Measure quality of life at baseline, 6 weeks, 6 months after the initiation of adjuvant
therapy, and at the end of study participation (recurrence or completing study treatments)
using a validated quality of life questionnaire (European Organization for Research and
Treatment of Cancer [EORTC] QLQ-C30).

EXPLORATORY OBJECTIVES:

I. Perform molecular profiling on available tissue specimens obtained at the time of initial
surgical resection (formalin-fixed paraffin-embedded or frozen tissues) to identify genomic
alterations in primary tumors that are associated with the clinical end points. II. Evaluate
markers to detect ACC recurrence or predict response to therapy (including steroid hormones
and precursors, circulating tumor cells, and micro ribonucleic acid [microRNA]).

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM A: Participants receive mitotane orally (PO) daily on days 1-21. Courses repeat every 21
days for 2 years in the absence of disease progression or unacceptable toxicity.

ARM B: Participants receive mitotane as in Arm A. Participants also receive cisplatin
intravenously (IV) over 2 hours on day 1 and etoposide IV over 2 hours on days 1-3. Treatment
repeats every 21 days for up to 4 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, participants are followed up every 6 months.

Inclusion Criteria:

- Have a histologically confirmed diagnosis of ACC (Weiss score of >= 3).
(LinWeiss-Bisceglia system will be used for oncocytic ACC).

- Have a high risk of relapse defined as: Stage I-III ACC (according to the European
Network for the Study of Adrenal Tumors [ENSAT] classification) within 90 days of
surgical resection of primary tumor with curative intent with either microscopically
complete resection (R0, defined as no evidence of microscopic residual disease
according to surgical reports, histopathology, and perioperative imaging),
microscopically positive margins (R1), or undetermined margins (RX, based on surgical
or pathological reports without unequivocal evidence of metastasis in the
perioperative imaging). Each participating center will determine the pathological
stages and resection margins AND Ki67 > 10% (to be determined by an experienced
pathologist in each participating center and preferably via quantitative imaging
analysis).

- Have perioperative imaging (computed tomography [CT] with contrast, magnetic resonance
imaging [MRI] of the chest/abdomen/pelvis, or fluorodeoxyglucose positron emission
tomography [FDG-PET] CT) without 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.

- Have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

- Be able to comply with the protocol procedures.

- Provide written informed consent.

Exclusion Criteria:

- The time between primary surgery and randomization > 90 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 m^2). GFRs will be calculated according to the validated formula
(Modification of Diet in Renal Disease [MDRD]).

- They have significant liver insufficiency (serum bilirubin > 2 times the upper normal
range)

- They have significant liver insufficiency (serum alanine aminotransferase [ALT] or
aspartate aminotransferase [AST] > 3 times the upper normal range)

- Impaired bone marrow reserve (neutrophils < 1000/mm^3)

- Impaired bone marrow reserve (platelets < 100,000/mm^3)

- Pregnancy or breast feeding.

- They have known congestive heart failure (ejection fraction < 45%). In patients with a
history of cardiac disease, a baseline two-dimensional echocardiogram is needed as
standard of care 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.