Surgery Plus Chemotherapy (Doxorubicin, Vincristine and Etoposide), Mitotane, and Tariquidar to Treat Adrenocortical Cancer

NCT00071058 | Completed Phase 2 Results

• 2 other identifiers: 04001104-C-0011
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine the safety and effectiveness of treating adrenocortical cancer with combination chemotherapy using doxorubicin, vincristine, and etoposide in addition to the drugs mitotane and tariquidar and, when possible, surgery. Adrenocortical cancer cells have a large amount of a protein called P-glycoprotein that "pumps" anti-cancer drugs out of the cells, decreasing their effectiveness. Continuous infusions of doxorubicin, vincristine, and etoposide may improve chemotherapy results by blocking the P-glycoprotein pump, as may use of tariquidar, an experimental drug that is known to block the P-glycoprotein pump. Patients 18 years of age and older with adrenocortical cancer that has recurred, spread, or cannot be treated surgically may be eligible for this study. Candidates will be screened with a medical history and physical examination; review of pathology slides; blood tests; electrocardiogram (EKG); imaging tests, including computed tomography (CT) of the chest, abdomen and pelvis; chest x-ray; and possibly a bone scan or other imaging tests needed to evaluate the cancer, urine studies, and an echocardiogram. Also, a biopsy (removal of a small sample of tumor tissue) may be required if a specimen is not available to confirm the cancer. Participants will undergo the following tests and procedures:

• Tumor biopsy. Before starting chemotherapy, a small piece of tumor is removed to study the P-glycoprotein pump and to determine the tumor genetics.
• Blood draw. Blood is drawn before treatment begins to establish baseline levels for future blood tests.
• Central venous catheter placement. A specially trained physician places a plastic tube into a major vein in the chest. The tube is used to give the study drugs and other medications and to withdraw blood samples. It can stay in the body for months or be removed after each treatment is completed. The tube placement is done under a local anesthetic in the radiology department or operating room.
• Chemotherapy. Treatment cycles are 21 days. Doxorubicin, vincristine, and etoposide are given through the central venous catheter by an infusion pump continuously over 96 hours starting day 1 of each cycle. The dose of these drugs may be increased or decreased from cycle to cycle, based on side effects. Mitotane is given in pill form starting day 1 of cycle 1 and is taken every day throughout the entire study. The mitotane dose is gradually increased as long as the side effects are tolerable. Tariquidar is given through the central venous catheter as a 30-minute infusion on days 1 and 3 of every cycle. The tariquidar dose remains the same throughout the study. Treatment will continue for two cycles after all the cancer is gone, or until surgery is done to remove some or all of the remaining cancer, or, if surgery is not an option, until the cancer has grown to where it is defined as progressive disease.
• Nuclear scans. A nuclear scan is done before treatment begins and again on day 1 or day 3 of the first treatment cycle after administration of tariquidar to evaluate the P glycoprotein response to treatment.
• Computed tomography (CT) scans. These scans are done every two treatment cycles to follow disease progress.
• Surgery. Surgery to remove areas of cancer may be considered at any point during the study (including before beginning treatment), if it is deemed beneficial. Treatment with the study drugs will begin or resume after surgery. The length of treatment will depend on the response to treatment before the surgery and on whether there is any cancer remaining after the surgery.

Conditions

Adrenal Cortex Neoplasms

Keywords

P-glycoprotein Inhibition; Drug Resistance Reversal; Pharmacodynamics; Molecular Target; Endocrine Cancer; Adrenocortical Cancer; ACC; Adrenocortical Tumor

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With a Partial or Complete Response

  Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response is defined as the disappearance of all signs and symptoms of tumor for a period of at least 4 weeks. Partial response is defined as at least a 30% decrease in the sum of the longest diameter of all measured lesions lasting for a period of 4 weeks.

  Every 6 weeks for up to a year

Secondary Outcomes (1)

• Number of Participants With Adverse Events

  60 months, 19 days

Study Arms (1)

Surgery plus chemotherapy

EXPERIMENTAL

Surgical resection can be performed at the time of study entry, when patients have a mixed response, or if their tumors respond to chemotherapy. Surgical resection will be followed by chemotherapy with 2 grams oral dose daily of mitotane on cycle 1, day 1, 6 mg/m\^2 continuous intravenous infusion doxorubicin over 96 hours days 1-4, 0.18 mg/m\^2 continuous intravenous infusion vincristine over 96 hours days 1-4, and 36 mg/m\^2 continuous intravenous infusion etoposide over 96 hours days 1-4, and 150 mg tariquidar through central venous catheter over 30 minutes on days 1 and 3.

Drug: XR9576 (Tariquidar)

Interventions

XR9576 (Tariquidar) DRUG

Also known as: 150 mg tariquidar through central venous catheter over 30 minutes on days 1 and 3.

Surgery plus chemotherapy

Eligibility Criteria

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

You may qualify if:

• Pathologic confirmation of adrenocortical cancer by the Laboratory of Pathology, NCI
• Diagnosis of recurrent, metastatic, or primary unresectable adrenocortical carcinoma.
• Measurable disease at presentation.
• A life expectancy of at least 3 months and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
• Age greater than or equal to 18 years.
• Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in the case of nitrosourea) prior to enrollment date.
• Last radiotherapy treatment 4 weeks prior to starting treatment with this protocol and there must be sites of measurable disease that did not receive radiation.
• Prior mitotane therapy is allowed. Patients do not need to be off mitotane therapy prior to starting this protocol.
• Organ and marrow function as defined below:
• Total bilirubin less than or equal to 1.5 times ULN (upper limit of normal), unless the patient meets the criteria for Gilbert's Syndrome,
• Aspartate aminotransferase (AST) less than or equal to 3 times ULN, Alanine aminotransferase (ALT) less than or equal to 3 times ULN
• Creatinine clearance greater than or equal to 40 ml/min (measured in a timed urine collection) or serum creatinine less than or equal to 1.6 mg/dl
• Absolute neutrophil count greater than or equal to 1000/mm\^3,
• Platelet count greater than or equal to 100,000/mm\^3
• Ability to understand and sign an informed consent document.

You may not qualify if:

• Patients with adrenocortical tumors potentially curable by surgical excision alone as determined by the Principal Investigator in discussions with the surgical consultants.
• Uncontrolled illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, seizure disorder, or psychiatric illness that may limit compliance with study requirements. These illnesses may be exacerbated by chemotherapy.
• Untreated brain metastases (or local treatment of brain metastases within the last 6 months) due to the poor prognosis of these patients and difficulty ascertaining the cause of neurologic toxicities.
• Pregnancy due to the possible adverse effects on the developing fetus.
• Lactating women who are breast-feeding due to the possibility of transmitting chemotherapy to the child.
• The presence of a second malignancy, other than squamous cell carcinoma of the skin or in situ cervical cancer because it will complicate the primary objective of the study. Cancer survivors who have been free of disease for at least two years can be enrolled in this study.
• Currently receiving treatment (which cannot be discontinued) with the following agents: diltiazem, nicardipine, phenothiazines, phenytoin, or verapamil because these are Pgp inhibitors and will interfere with the primary objective of the study.
• Ejection fraction less than 40% as determined by multi-gated acquisition scan (MUGA), echocardiogram (Echo), or cardiac magnetic resonance imaging (MRI) in patients with a clinical history suggestive of systolic dysfunction.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Cancer Institute (NCI)

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Cohn K, Gottesman L, Brennan M. Adrenocortical carcinoma. Surgery. 1986 Dec;100(6):1170-7.

  PMID: 3787475 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Adrenal Cortex Neoplasms; Endocrine Gland Neoplasms

Interventions

tariquidar

Condition Hierarchy (Ancestors)

Adrenal Gland Neoplasms; Neoplasms by Site; Neoplasms; Adrenal Cortex Diseases; Adrenal Gland Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Antonio Fojo, M.D.
• Organization: National Cancer Institute, National Institutes of Health

FojoT@mail.nih.gov

301-496-2631

Study Officials

• Antonio Fojo, M.D.

  National Cancer Institute, National Institutes of Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH

Study Record Dates

• First Submitted: October 9, 2003
• First Posted: October 10, 2003
• Study Start: October 1, 2003
• Primary Completion: November 1, 2009
• Study Completion: November 1, 2009
• Last Updated: September 18, 2012
• Results First Posted: September 12, 2012

Record last verified: 2012-09

Locations

US (1)