International Study: Comparison of Two Treatments for Adrenocortical Cancer
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on October 19, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Adenocortical Cancer
Intervention: Mitotane (Drug); Streptozocin (Drug); Doxorubicin (Drug); Etoposide (Drug); Cisplatin (Drug)
Phase: Phase 3
Status: Recruiting
Sponsored by: National Cancer Institute (NCI) Overall contact:
NCI Referral Office, Phone: 1-888-NCI-1937, Email: ncicssc@mail.nih.gov
Summary
Background:
- There is no medical consensus about the best treatment for advanced adrenocortical
cancer (ACC) that cannot successfully be treated with surgery alone.
- In 2003, the International Consensus Conference on Adrenal Cancer recommended two chemotherapy regimens - etoposide, doxorubicin, cisplatin plus mitotane and
streptozotocin plus mitotane- as the best choices until better data could be obtained.
All the drugs in the two options have been shown effective against advanced ACC, but
they have different side effects.
Objectives:
- To determine which of the chemotherapy regimens described above is best to start with
in patients with ACC that cannot be surgically removed.
- To determine if there is a way to identify which patients will respond to a certain
therapy.
Eligibility:
- Patients 18 years of age and older from the USA, Scandinavia, Germany, Italy, France, The
Netherlands, Belgium, the UK, Canada and Australia who have adrenocortical cancer that
cannot be cured with surgery alone.
Design:
- Chemotherapy: Patients are randomly assigned to start with one of the two study
regimens. Patients whose tumor continues to grow during treatment are offered the
alternative therapy. All patients receive daily tablets of mitotane. In addition, they
have one of the following two regimens:
- Streptozotocin every 3 weeks for up to six cycles. The first cycle is given on days 1,
2, 3, 4 and 5 and subsequent cycles are given on day 1 only.
- Cisplatin plus etoposide plus doxorubicin every 4 weeks for up to six cycles.
Doxorubicin is given on day 1, etoposide is given on days 2, 3 and 4 and cisplatin is
given on days 3 and 4.
- CT scans of the chest, abdomen and pelvis approximately once every 8 weeks.
- Physical examination, routine blood tests and a check of side effects at the start of
each treatment cycle.
- Blood test to determine if the hormones produced by some adrenocortical cancers have
any effect on the immune system.
- Analysis of genetic markers in blood and tumor tissue for comparison with tumor growth
and patient survival to determine if this can help identify which patients will respond
to a certain therapy.
- Optional procedures:
- Storage of blood and tissue samples for future research.
- Completion of quality-of-life questionnaires every 2 months.
Clinical Details
Official title: First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) Etoposide, Doxorubicin, Cisplatin and Mitotane vs Streptozotocin and Mitotane
Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study
Primary outcome: Disease Response
Secondary outcome: QOL, Compare TLP, Best overall RR, duration of response, # of disease free pts impact of mitotane levels on response, Assess effects of both schemas as 2nd line tx.
Detailed description:
Background:
- Adrenocortical cancer (ACC) is a rare disease with an extremely poor prognosis.
- Treatment of advanced ACC has never been adequately standardized and the choice of
therapy is based on personal experience and data from uncontrolled trials.
- Previous studies including streptozotocin plus mitotane (Sz/M) regimen and etoposide,
doxorubicin, cisplatin plus mitotane (EDP/M) regimen appear to have some activity in
ACC and were recommended as best choices until better data arise.
- Previous reports with EDP/M suggest that it is possible to achieve with this regimen a
higher response rate than with the Sz/M regimen, but that it may be more toxic. No
survival data is available for comparison from these studies.
Objectives:
- To investigate whether etoposide, doxorubicin, cisplatin plus mitotane (EDP/M) as first
line treatment will prolong survival as compared to streptozocin plus mitotane (Sz/M) as
first line treatment in advanced ACC.
Eligibility:
- Histologically confirmed diagnosis of adrenocortical carcinoma.
- Locally advanced or metastatic disease not amenable to radical surgery resection (Stage
III-IV).
- Radiologically measurable disease.
- ECOG performance status 0 - 2.
- Life expectancy greater than 3 months.
- Age greater than or equal to 18 years.
- Adequate bone marrow reserve (neutrophils greater than 1500/mm(3) and platelets greater
than 100,000/mm(3)).
- Previous palliative surgery, radiotherapy or radiofrequency ablation is acceptable as
long as disease that can be monitored and verified radiologically has not been treated.
Design:
- Phase III, randomized, open-label, multi-national trial.
- 300 patients will be accrued for the study.
- Patients will be randomized to receive therapy with etoposide, doxorubicin, cisplatin
plus mitotane (EDP/M) or streptozotocin plus mitotane (Sz/M) as first line treatment.
- Evaluation of response is scheduled every 8 weeks in the first 6 months after beginning
first line and second line treatment, respectively, and afterwards every 12 weeks. In
case of documented disease progression or unacceptable toxicity, subjects will be
switched to the alternative regimen.
Eligibility
Minimum age: 18 Years.
Maximum age: 80 Years.
Gender(s): Both.
Criteria:
- INCLUSION CRITERIA:
Clinical inclusion criteria
- Histologically confirmed diagnosis of adrenocortical carcinoma.
- Locally advanced or metastatic disease not amenable to radical surgery resection
(Stage III-IV).
Other inclusion criteria
- Radiologically monitorable disease.
- ECOG performance status 0-2.
- Life expectancy greater than 3 months.
- Age greater than or equal to 18 years.
- Adequate bone marrow reserve (neutrophils greater than or equal to 1500/mm(3) and
platelets greater than or equal to 100. 000/mm(3)).
- Effective contraception in pre-menopausal female and male patients.
- Patient's written informed consent.
- Ability to comply with the protocol procedures (including availability for follow-up
visits).
- Previous palliative surgery, radiotherapy or radiofrequency ablation is acceptable as
long as radiologically monitorable disease is verifiably afterwards.
EXCLUSION CRITERIA:
- History of prior malignancy, except for cured non-melanoma skin cancer, cured in situ
cervical carcinoma, or other cancers treated with no evidence of disease for at least
five years.
- Previous cytotoxic chemotherapy (prior therapy with mitotane is allowed) for
adrenocortical carcinoma.
- Renal insufficiency (serum creatinine greater than or equal to 2 mg/dl or creatinine
clearance less than or equal to 50 ml/min). (see NCI Appendix).
- Hepatic insufficiency (serum bilirubin greater than or equal to 2 times the
institutional upper limit of normal range and/or serum transaminases greater than or
equal to 3 times the institutional upper limit of normal range; exception: in
patients on mitotane transaminase levels up to 5 times the institutional upper limit
of normal range are acceptable) (see NCI Appendix).
- Pregnancy or breast feeding.
- Known hypersensitivity to any drug included in the treatment protocol.
- Presence of active infection.
- Any other severe clinical condition that in the judgment of the local investigator
would place the patient at undue risk or interfere with the study completion.
- Decompensated heart failure (ejection fraction less than 50 percent), myocardial
infarction or revascularization procedure during the last 6 months, unstable angina
pectoris, and uncontrolled cardiac arrhythmia.
- Current treatment with other experimental drugs and/or previous participation in
clinical trials with other experimental agents for adrenocortical carcinoma.
- Prisoners
Locations and Contacts
NCI Referral Office, Phone: 1-888-NCI-1937, Email: ncicssc@mail.nih.gov
University of Wuerzburg, Wuerzburg, Germany; Recruiting
National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
Additional Information
NIH Clinical Center Detailed Web Page
Related publications: Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. Abraham J, Bakke S, Rutt A, Meadows B, Merino M, Alexander R, Schrump D, Bartlett D, Choyke P, Robey R, Hung E, Steinberg SM, Bates S, Fojo T. A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycoprotein antagonist. Cancer. 2002 May 1;94(9):2333-43. Allolio B, Hahner S, Weismann D, Fassnacht M. Management of adrenocortical carcinoma. Clin Endocrinol (Oxf). 2004 Mar;60(3):273-87. Review.
Starting date: September 2008
Ending date: June 2011
Last updated: September 16, 2009
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