Mitotane With or Without Cisplatin and Etoposide After Surgery in Treating Patients With Stage I-III Adrenocortical Cancer With High Risk of Recurrence

A Randomized Registry Trial of Adjuvant Mitotane vs. Mitotane With Cisplatin/Etoposide After Primary Surgical Resection of Localized Adrenocortical Carcinoma With High Risk of Recurrence (ADIUVO-2 Trial)

This phase III trial studies how well mitotane alone works compared to mitotane with cisplatin and etoposide when given after surgery in treating patients with adrenocortical cancer that has a high risk of coming back (recurrence). 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 patients with adrenocortical carcinoma.

Study Overview

• Status: Recruiting
• Conditions: ENSAT Stage I Adrenal Cortex Carcinoma; ENSAT Stage II Adrenal Cortex Carcinoma; ENSAT Stage III Adrenal Cortex Carcinoma
• Intervention / Treatment: Drug: Etoposide; Other: Quality-of-Life Assessment; Drug: Cisplatin; Drug: Mitotane

Detailed Description

PRIMARY OBJECTIVE:

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) versus (vs.) late start (> 6 weeks from surgery) of adjuvant therapy on clinical outcomes.

IV. Assess serious adverse events. 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: Patients are randomized to 1 of 2 arms.

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

ARM B: Patients receive mitotane as in Arm A. Patients 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 cycles in the absence of disease progression or unacceptable toxicity.

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

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Mouhammed Habra; Phone Number: 713-792-2841; Email: mahabra@mdanderson.org

Study Locations

• France
  • Paris, France, 75014
    • Not yet recruiting
    • Hôpital Cochin
    • Contact: Rossella Libé; Phone Number: +33 1 58 41 32 49; Email: rossella.libe@aphp.fr
• Poland
  • Gliwice, Poland, 44-102
    • Recruiting
    • Maria Sklodowska-Curie National Research Institute of Oncology
    • Contact: Agnieszka Kotecka-Blicharz; Email: Agnieszka.Kotecka-Blicharz@io.gliwice.pl
    • Principal Investigator: Barbara Jarzab, MD
• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan Comprehensive Cancer Center
      • Contact: Francis P. Worden; Email: fworden@umich.edu
      • Principal Investigator: Francis P. Worden
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Active, not recruiting
      • Siteman Cancer Center at Washington University
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • M D Anderson Cancer Center
      • Contact: Mouhammed A. Habra; Phone Number: 713-792-2841; Email: mahabra@mdanderson.org
      • Principal Investigator: Mouhammed A. Habra

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 8 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.
• Gross residual disease after surgery (R2 resection)
• High suspicion for metastatic disease on perioperative imaging
• 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).
• 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%). The extent of cardiac testing will depend on the judgment of the local principal investigator (PI). In general, in patients with a history of cardiac disease, it is recommended to obtain a baseline two-dimensional echocardiogram 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. Cardiac imaging and EKG may not be needed in patients assigned to mitotane who do not have prior cardiac history and have low suspicion for cardiac symptoms to reflect standards of clinical practice. Similarly, utilizing cardiac imaging and EKG within the past 12 months is permitted if there is no suspicion for cardiac issues.
• 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, in the judgment of the investigator, pose excess risk associated with study participation or administration of the involved drugs or that, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (mitotane); Patients receive mitotane PO daily on days 1-21. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity.	Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Mitotane; Given PO; Other Names: DDD; Lysodren; (o,p)-DDD; 1, 1-Dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane; 1-Chloro-2-[2,2-dichloro-1-(4-chlorophenyl)ethyl]benzene; 2, 2-Bis(2-chlorophenyl-4-chlorophenyl)-1,1-dichloroethane; 2, 4''-Dichlorodiphenyldichloroethane; CB 313; CB-313; Chloditan; Chlodithane; Ethane, 2-(o-chlorophenyl)-2-(p-chlorophenyl)-1,1-dichloro-; Khloditan; Lisodren; Mytotan; o,p'' - DDD; o,p''-DDD; Ortho,para-DDD; WR-13045
Experimental: Arm B (mitotane, etoposide, cisplatin); Patients receive mitotane as in Arm A. Patients also receive cisplatin 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 cycles in the absence of disease progression or unacceptable toxicity.	Drug: Etoposide; Given IV; Other Names: Demethyl Epipodophyllotoxin Ethylidine Glucoside; EPEG; Lastet; Toposar; Vepesid; VP 16; VP 16-213; VP-16; VP-16-213; VP16; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Cisplatin; Given IV; Other Names: CDDP; Cis-diamminedichloridoplatinum; Cismaplat; Cisplatinum; Neoplatin; Platinol; Abiplatin; Blastolem; Briplatin; Cis-diammine-dichloroplatinum; Cis-diamminedichloro Platinum (II); Cis-diamminedichloroplatinum; Cis-dichloroammine Platinum (II); Cis-platinous Diamine Dichloride; Cis-platinum; Cis-platinum II; Cis-platinum II Diamine Dichloride; Cisplatina; Cisplatyl; Citoplatino; Citosin; Cysplatyna; DDP; Lederplatin; Metaplatin; Placis; Plastistil; Platamine; Platiblastin; Platiblastin-S; Platinex; Platinol- AQ; Platinol-AQ; Platinol-AQ VHA Plus; Platinoxan; Platinum; Platinum Diamminodichloride; Platiran; Platistin; Platosin; Peyrone''s Chloride; Peyrone''s Salt; Drug: Mitotane; Given PO; Other Names: DDD; Lysodren; (o,p)-DDD; 1, 1-Dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane; 1-Chloro-2-[2,2-dichloro-1-(4-chlorophenyl)ethyl]benzene; 2, 2-Bis(2-chlorophenyl-4-chlorophenyl)-1,1-dichloroethane; 2, 4''-Dichlorodiphenyldichloroethane; CB 313; CB-313; Chloditan; Chlodithane; Ethane, 2-(o-chlorophenyl)-2-(p-chlorophenyl)-1,1-dichloro-; Khloditan; Lisodren; Mytotan; o,p'' - DDD; o,p''-DDD; Ortho,para-DDD; WR-13045

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence-free survival (RFS)	Starting from the date of randomization until documentation of radiological evidence of local recurrence, radiological evidence of distant recurrence, or death from any cause (whichever occurs first), RFS will be compared using the log-rank test between the two arms.	From the time of randomization up to 2 years
Local recurrence of adrenocortical carcinoma (ACC)		Up to 6 months
Distant recurrence of ACC		Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Overall survival will be compared using the log-rank test.	From the time of randomization up to 2 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: Assistance Publique - Hôpitaux de Paris; National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mouhammed A Habra, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center Website

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2018
• Primary Completion (Estimated): January 22, 2025
• Study Completion (Estimated): January 22, 2025

Study Registration Dates

• First Submitted: June 28, 2018
• First Submitted That Met QC Criteria: June 28, 2018
• First Posted (Actual): July 11, 2018

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 9, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Disease Attributes; Endocrine Gland Neoplasms; Adrenal Gland Diseases; Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenal Cortex Diseases; Carcinoma; Recurrence; Adrenocortical Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Keratolytic Agents; Etoposide; Etoposide phosphate; Cisplatin; Podophyllotoxin; Mitotane
• Other Study ID Numbers: 2017-0948 (Other Identifier: M D Anderson Cancer Center); NCI-2018-01101 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes