Adjuvant Chemotherapy vs. Observation/Mitotane After Primary Surgical Resection of Localized Adrenocortical CarcInoma

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Brief Title

Adjuvant Chemotherapy vs. Observation/Mitotane After Primary Surgical Resection of Localized Adrenocortical CarcInoma

Official Title

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

Brief Summary

      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).
    

Detailed Description

      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.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Comparison of the recurrence-free survival (RFS) status in patientis treated with adiuvant chemotherapy with or without mitotane (arm A) versus no treatment or adjuvant mitotane (arm B).

Secondary Outcome

 Assessment of overal survival

Condition

Adrenocortical Carcinoma

Intervention

Cisplatin plus Etoposide

Study Arms / Comparison Groups

 A - adjuvant therapy
Description:  adjuvant therapy with four cycles of cisplatin plus etoposide +/- mitotane according to investigator's preference versus

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

240

Start Date

July 1, 2018

Completion Date

June 30, 2021

Primary Completion Date

June 30, 2020

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Alfredo Berruti, MD, 0039 030 399 5410, [email protected]

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT03723941

Organization ID

ACACIA

Secondary IDs

ADIUVO-2

Responsible Party

Principal Investigator

Study Sponsor

Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia


Study Sponsor

Alfredo Berruti, MD, Principal Investigator, ASST Spedali Civili di Brescia


Verification Date

October 2018