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

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ClinicalTrials.gov Identifier: NCT03723941
Recruitment Status : Recruiting
First Posted : October 30, 2018
Last Update Posted : October 30, 2018
Sponsor:
Information provided by (Responsible Party):
Alfredo Berruti, Azienda Ospedaliera Spedali Civili di Brescia

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).

Condition or disease Intervention/treatment Phase
Adrenocortical Carcinoma Drug: Cisplatin plus Etoposide Other: Observation or Mitotane Phase 3

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Prospective, randomized, open-label, stratified, nation-based multi-center, phase III trial for patients with ACC and Ki67≥10% after resection with curative intent
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 1, 2018
Estimated Primary Completion Date : June 30, 2020
Estimated Study Completion Date : June 30, 2021


Arm Intervention/treatment
Experimental: A - adjuvant therapy
adjuvant therapy with four cycles of cisplatin plus etoposide +/- mitotane according to investigator's preference versus
Drug: Cisplatin plus Etoposide

Etoposide 100 mg/m2 will be administered IV on days 1, 2, 3 diluted in 500 mL of isotonic NaCl or 5% dextrose.

Cisplatin, 80 mg/m2 will be administered IV on day 1, diluted in 500 mL of isotonic NaCl.

Other Name: Adjuvant Chemotherapy

Other: Observation or Mitotane
Observation or mitotane alone according to the investigator's preference

B - observation or mitotane alone
observation or mitotane alone according to the investigator's preference
Other: Observation or Mitotane
Observation or mitotane alone according to the investigator's preference




Primary Outcome Measures :
  1. 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). [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months ]
    Evaluation of recurrence-free survival (RFS). Recurrence will be objectively assessed every 16 weeks by imaging the chest/abdomen/pelvis by either computed tomography (CT; with slice thickness of 5 mm or less) or magnetic resonance imaging (MRI). Suspected lesions will be accurately measured in at least one dimension (the longest diameter in the plane of measurement will be recorded). Soft tissue lesions must have a minimum size of 10 mm, and suspected malignant lymph nodes must be more than 15 mm (short axis) to be considered pathological.


Secondary Outcome Measures :
  1. Assessment of overal survival [ Time Frame: From date of randomization until the date of death from any cause, assessed up to 36 months ]
    defined as the time interval between the date of randomization and the date of death from any cause.

  2. Assessment of toxicity and adverse events [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months ]
    Toxicity and adverse events will be graded according to the NCI-CTCAE (version 4.03).

  3. Assessment of the predictive role of Ki67 expression for chemotherapy efficacy [ Time Frame: Ki67 expression evaluated at the screening phase ]
    Histological evaluation of KI67 expression on basal tumor tissue sections and correlation to chemotherapy efficacy

  4. Assessment of the predictive role of histopathologic characteristics (Weiss-score) for chemotherapy efficacy [ Time Frame: Weiss score identified at the screening phase ]
    Weiss score will be identified on basal tumor tissue resection based on the original Weiss criteria for malignancy (Am J Surg Pathol 1984;8:163), and will be correlated to chemotherapy efficacy. The Weiss scoring system is based on the recognition at light microscopy of nine morphological parameters: three of them are related to tumor structure, namely presence of eosinophilic ("dark") cytoplasm in more than 75% of tumor cells, of a "patternless" diffuse architecture, and of necrosis; three others are related to cytological features, namely presence of nuclear atypia, of mitotic index above 5 per 50 high-power fields, and of atypical mitoses; the remaining three are related to invasive tumor properties, including sinusoidal, venous, and capsular invasion. A diagnosis of malignancy is achieved if at least three parameters are identified out of 9 (scale from 0 to 9).


Other Outcome Measures:
  1. BioBank [ Time Frame: Baseline ]
    Available tissue specimens (formalin-fixed paraffin-embedded or frozen tissues) plus one sample of serum, plasma and urine, will be collected before randomization for each patient enrolled in this study.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03723941


Contacts
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Contact: Alfredo Berruti, MD 0039 030 399 5410 alfredo.berruti@gmail.com

Locations
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Italy
ASST Spedali Civili di Brescia Recruiting
Brescia, BS, Italy, 25123
Contact: Alfredo Berruti, MD    0039 030 399 5410    alfredo.berruti@gmail.com   
Sponsors and Collaborators
Azienda Ospedaliera Spedali Civili di Brescia
Investigators
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Principal Investigator: Alfredo Berruti, MD ASST Spedali Civili di Brescia

Publications of Results:

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Responsible Party: Alfredo Berruti, Head of Oncology Unit, Azienda Ospedaliera Spedali Civili di Brescia
ClinicalTrials.gov Identifier: NCT03723941     History of Changes
Other Study ID Numbers: ACACIA
ADIUVO-2 ( Other Identifier: MD Anderson )
First Posted: October 30, 2018    Key Record Dates
Last Update Posted: October 30, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alfredo Berruti, Azienda Ospedaliera Spedali Civili di Brescia:
Adrenocortical Carcinoma
Adjuvant Chemotherapy
Additional relevant MeSH terms:
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Carcinoma
Adrenocortical Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Adrenal Cortex Neoplasms
Adrenal Gland Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Adrenal Cortex Diseases
Adrenal Gland Diseases
Endocrine System Diseases
Cisplatin
Etoposide
Etoposide phosphate
Mitotane
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Hormonal