Houston, Texas 77030


Purpose:

This phase III trial studies how well mitotane alone works compared to mitotane with cisplatin and etoposide when given after surgery in treating participants with adrenocortical cancer that has a high risk of coming back. Cortisol can cause the growth of adrenocortical tumor cells. Antihormone therapy, such as mitotane, may lessen the amount of cortisol made by the body. Drugs used in chemotherapy, such as cisplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether mitotane alone or mitotane with cisplatin and etoposide after surgery works better in treating participants with adrenocortical carcinoma.


Study summary:

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.


Criteria:

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.


NCT ID:

NCT03583710


Primary Contact:

Principal Investigator
Mouhammed Habra
M.D. Anderson Cancer Center

Mouhammed Habra
Phone: 713-792-2841
Email: mahabra@mdanderson.org


Backup Contact:

N/A


Location Contact:

Houston, Texas 77030
United States

Mouhammed A. Habra
Phone: 713-792-2841
Email: mahabra@mdanderson.org

Site Status: Recruiting


Data Source: ClinicalTrials.gov

Date Processed: February 04, 2019

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