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

NCT03583710

Description:

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.

Related Conditions:
  • Adrenal Cortex Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Mitotane With or Without Cisplatin and Etoposide After Surgery in Treating Patients With Stage I-III Adrenocortical Cancer With High Risk of Recurrence
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 2017-0948
  • SECONDARY ID: NCI-2018-01101
  • SECONDARY ID: 2017-0948
  • NCT ID: NCT03583710

Conditions

  • ENSAT Stage I Adrenal Cortex Carcinoma
  • ENSAT Stage II Adrenal Cortex Carcinoma
  • ENSAT Stage III Adrenal Cortex Carcinoma

Interventions

DrugSynonymsArms
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm B (mitotane, etoposide, cisplatin)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Arm B (mitotane, etoposide, cisplatin)
Mitotane(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, DDD, Ethane, 2-(o-chlorophenyl)-2-(p-chlorophenyl)-1,1-dichloro-, Khloditan, Lisodren, Lysodren, Mytotan, o,p'' - DDD, o,p''-DDD, Ortho,para-DDD, WR-13045Arm A (mitotane)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (mitotane)ExperimentalPatients 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.
  • Mitotane
Arm B (mitotane, etoposide, cisplatin)ExperimentalPatients 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.
  • Cisplatin
  • Etoposide
  • Mitotane

Eligibility 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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recurrence-free survival (RFS)
Time Frame:From the time of randomization up to 2 years
Safety Issue:
Description: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.

Secondary Outcome Measures

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

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

April 26, 2021