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

NCT03723941 | Completed Phase 3

• 2 other identifiers: ACACIAADIUVO-2
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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).

Conditions

Adrenocortical Carcinoma

Keywords

Adrenocortical Carcinoma; Adjuvant Chemotherapy

Outcome Measures

Primary Outcomes (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).

  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.

  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

Secondary Outcomes (4)

• Assessment of overal survival

  From date of randomization until the date of death from any cause, assessed up to 36 months

• Assessment of toxicity and adverse events

  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

• Assessment of the predictive role of Ki67 expression for chemotherapy efficacy

  Ki67 expression evaluated at the screening phase

• Assessment of the predictive role of histopathologic characteristics (Weiss-score) for chemotherapy efficacy

  Weiss score identified at the screening phase

Other Outcomes (1)

• BioBank

  Baseline

Study Arms (2)

A - adjuvant therapy

EXPERIMENTAL

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

Drug: Cisplatin plus Etoposide; Other: Observation or Mitotane

B - observation or mitotane alone

OTHER

observation or mitotane alone according to the investigator's preference

Other: Observation or Mitotane

Interventions

Cisplatin plus Etoposide DRUG

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.

Also known as: Adjuvant Chemotherapy

A - adjuvant therapy

Observation or Mitotane OTHER

Observation or mitotane alone according to the investigator's preference

A - adjuvant therapy; B - observation or mitotane alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia: lead

Study Sites (1)

ASST Spedali Civili di Brescia

Brescia, BS, 25123, Italy

Location

Related Publications (17)

• Kebebew E, Reiff E, Duh QY, Clark OH, McMillan A. Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J Surg. 2006 May;30(5):872-8. doi: 10.1007/s00268-005-0329-x.

  PMID: 16680602 RESULT

• Grubbs EG, Callender GG, Xing Y, Perrier ND, Evans DB, Phan AT, Lee JE. Recurrence of adrenal cortical carcinoma following resection: surgery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol. 2010 Jan;17(1):263-70. doi: 10.1245/s10434-009-0716-x. Epub 2009 Oct 23.

  PMID: 19851811 RESULT

• Beuschlein F, Weigel J, Saeger W, Kroiss M, Wild V, Daffara F, Libe R, Ardito A, Al Ghuzlan A, Quinkler M, Osswald A, Ronchi CL, de Krijger R, Feelders RA, Waldmann J, Willenberg HS, Deutschbein T, Stell A, Reincke M, Papotti M, Baudin E, Tissier F, Haak HR, Loli P, Terzolo M, Allolio B, Muller HH, Fassnacht M. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab. 2015 Mar;100(3):841-9. doi: 10.1210/jc.2014-3182. Epub 2015 Jan 5.

  PMID: 25559399 RESULT

• Berruti A, Baudin E, Gelderblom H, Haak HR, Porpiglia F, Fassnacht M, Pentheroudakis G; ESMO Guidelines Working Group. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 Oct;23 Suppl 7:vii131-8. doi: 10.1093/annonc/mds231. No abstract available.

  PMID: 22997446 RESULT

• Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007 Jun 7;356(23):2372-80. doi: 10.1056/NEJMoa063360.

  PMID: 17554118 RESULT

• Terzolo M, Fassnacht M, Ciccone G, Allolio B, Berruti A. Adjuvant mitotane for adrenocortical cancer--working through uncertainty. J Clin Endocrinol Metab. 2009 Jun;94(6):1879-80. doi: 10.1210/jc.2009-0120. No abstract available.

  PMID: 19494162 RESULT

• Hermsen IG, Fassnacht M, Terzolo M, Houterman S, den Hartigh J, Leboulleux S, Daffara F, Berruti A, Chadarevian R, Schlumberger M, Allolio B, Haak HR, Baudin E. Plasma concentrations of o,p'DDD, o,p'DDA, and o,p'DDE as predictors of tumor response to mitotane in adrenocortical carcinoma: results of a retrospective ENS@T multicenter study. J Clin Endocrinol Metab. 2011 Jun;96(6):1844-51. doi: 10.1210/jc.2010-2676. Epub 2011 Apr 6.

  PMID: 21470991 RESULT

• Terzolo M, Baudin AE, Ardito A, Kroiss M, Leboulleux S, Daffara F, Perotti P, Feelders RA, deVries JH, Zaggia B, De Francia S, Volante M, Haak HR, Allolio B, Al Ghuzlan A, Fassnacht M, Berruti A. Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection. Eur J Endocrinol. 2013 Jul 29;169(3):263-70. doi: 10.1530/EJE-13-0242. Print 2013 Sep.

  PMID: 23704714 RESULT

• Senkus E, Kyriakides S, Penault-Llorca F, Poortmans P, Thompson A, Zackrisson S, Cardoso F; ESMO Guidelines Working Group. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi7-23. doi: 10.1093/annonc/mdt284. Epub 2013 Aug 22. No abstract available.

  PMID: 23970019 RESULT

• Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L. Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer. Cancer. 1998 Nov 15;83(10):2194-200.

  PMID: 9827725 RESULT

• Bonacci R, Gigliotti A, Baudin E, Wion-Barbot N, Emy P, Bonnay M, Cailleux AF, Nakib I, Schlumberger M; Reseau Comete. Cytotoxic therapy with etoposide and cisplatin in advanced adrenocortical carcinoma. Br J Cancer. 1998 Aug;78(4):546-9. doi: 10.1038/bjc.1998.530.

  PMID: 9716042 RESULT

• Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardiere C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Muller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. doi: 10.1056/NEJMoa1200966. Epub 2012 May 2.

  PMID: 22551107 RESULT

• Tsuchiya R, Suzuki K, Ichinose Y, Watanabe Y, Yasumitsu T, Ishizuka N, Kato H. Phase II trial of postoperative adjuvant cisplatin and etoposide in patients with completely resected stage I-IIIa small cell lung cancer: the Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101). J Thorac Cardiovasc Surg. 2005 May;129(5):977-83. doi: 10.1016/j.jtcvs.2004.05.030.

  PMID: 15867769 RESULT

• Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, Stephens RJ, Dunant A, Torri V, Rosell R, Seymour L, Spiro SG, Rolland E, Fossati R, Aubert D, Ding K, Waller D, Le Chevalier T; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008 Jul 20;26(21):3552-9. doi: 10.1200/JCO.2007.13.9030. Epub 2008 May 27.

  PMID: 18506026 RESULT

• Oberg K. Chemotherapy and biotherapy in the treatment of neuroendocrine tumours. Ann Oncol. 2001;12 Suppl 2:S111-4. doi: 10.1093/annonc/12.suppl_2.s111.

  PMID: 11762335 RESULT

• Brix D, Allolio B, Fenske W, Agha A, Dralle H, Jurowich C, Langer P, Mussack T, Nies C, Riedmiller H, Spahn M, Weismann D, Hahner S, Fassnacht M; German Adrenocortical Carcinoma Registry Group. Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients. Eur Urol. 2010 Oct;58(4):609-15. doi: 10.1016/j.eururo.2010.06.024. Epub 2010 Jun 22.

  PMID: 20580485 RESULT

• Habra MA, Ejaz S, Feng L, Das P, Deniz F, Grubbs EG, Phan A, Waguespack SG, Ayala-Ramirez M, Jimenez C, Perrier ND, Lee JE, Vassilopoulou-Sellin R. A retrospective cohort analysis of the efficacy of adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma. J Clin Endocrinol Metab. 2013 Jan;98(1):192-7. doi: 10.1210/jc.2012-2367. Epub 2012 Nov 12.

  PMID: 23150683 RESULT

MeSH Terms

Conditions

Adrenocortical Carcinoma

Interventions

Cisplatin; Etoposide; Chemotherapy, Adjuvant; Observation; Mitotane

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Adrenal Cortex Diseases; Adrenal Gland Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Combined Modality Therapy; Therapeutics; Drug Therapy; Methods; Investigative Techniques; Hydrocarbons, Chlorinated; Hydrocarbons, Halogenated

Study Officials

• Alfredo Berruti, MD

  ASST Spedali Civili di Brescia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Oncology Unit

Model Details: Prospective, randomized, open-label, stratified, nation-based multi-center, phase III trial for patients with ACC and Ki67≥10% after resection with curative intent

Study Record Dates

• First Submitted: October 9, 2018
• First Posted: October 30, 2018
• Study Start: July 20, 2018
• Primary Completion: February 28, 2024
• Study Completion: May 30, 2024
• Last Updated: August 1, 2024

Record last verified: 2024-07

Locations

IT (1)