Protocol Number: 04-C-0011

Title:

A Study of Combination Chemotherapy & Surgical Resection in the Tx of Adrenocortical Cancer: Mitotane & Continuous Infusion Doxorubicin, Vincristine & Etoposide w/the P-glycoprotein Antagonist, Tariquidar (XR9576), Before & After Surgical Resection

Number:

04-C-0011

Summary:

Background:

-There are no effective systemic therapies for unresectable or relapsed adrenocortical cancer (ACC).

-High levels of expression of P-glycoprotein (Pgp) are observed in a majority of adrenocortical cancers.

-Pgp can function as a drug efflux pump lowering the intracellular concentrations of various drugs and has been implicated as a mechanism of drug resistance.

-A possible explanation for the failure of a prior NCI study (referred to as MAVE) to achieve a higher response rate may be that mitotane was unable to inhibit Pgp.

-Tariquidar (XR9576) has been proven to inhibit Pgp in humans with minimal toxicity alone or in combination with chemotherapy.

Objectives:

-Compare the response rate and progression free survival in recurrent, metastatic, or primary unresectable ACC treated with the combination of tariquidar, mitotane, and infusional doxorubicin, vincristine, and etoposide with the results observed in a previous trial with the same chemotherapy regimen without tariquidar.

-Determine the overall survival rate in the patients receiving tariquidar.

-Determine the safety of the combination of tariquidar, mitotane, and infusional doxorubicin, vincristine, and etoposide.

-Evaluate Pgp inhibition by using circulating CD 56+ mononuclear cells in an assay that measures the accumulation of rhodamine 123 and by performing 99mTc Sestamibi Scans to assess the accumulation of the radioisotope in tumors and in normal tissues in patients receiving tariquidar.

Eligibility:

-Age greater than 18.

-Pathological confirmation of adrenocortical cancer.

-Measurable disease at presentation.

-Last dose of chemotherapy or last radiotherapy treatment more than 4 weeks prior to starting treatment with this protocol.

-Prior mitotane therapy is allowed.

Design:

-Phase II study.

-Tariquidar will be administered over 30 minutes on days 1 and 3 on every 21 days cycle. Doxorubicin, vincristine, and etoposide will be continuously infused on days 1 through 4 every 21 days. Mitotane will be administered daily.

-Re-staging radiography will be performed every 2 cycles.

-Surgical excision of tumors can be performed on patients at the time of study entry, on patients whose tumor responds to chemotherapy and on patient with a mixed response if both the PI and Surgical Consult agree that this is the best strategy.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

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 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,

-AST less than or equal to 3 times ULN, 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.

Ability and willingness to follow the guidelines of the clinical protocol including visits to NCI, Bethesda, Maryland for treatment and follow up visits.

The effects of chemotherapy on the developing human fetus are potentially harmful therefore women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier methods) during the study and for a period of 1 month after the last dose of chemotherapy.

EXCLUSION CRITERIA:

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 MUGA, Echo, or cardiac MRI in patients with a clinical history suggestive of systolic dysfunction.

Special Instructions:

Currently Not Provided

Keywords:

P-glycoprotein Inhibition

Drug Resistance Reversal

Pharmacodynamics

Molecular Target

Endocrine Cancer

Adrenocortical Cancer

ACC

Adrenocortical Tumor

Recruitment Keyword(s):

None

Condition(s):

Adrenal Cortex Neoplasms

Investigational Drug(s):

XR9576 (Taruquidar)

Investigational Device(s):

None

Intervention(s):

Drug: XR9576 (Taruquidar)

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Plager JE. Carcinoma of the adrenal cortex: clinical description, diagnosis, and treatment. Int Adv Surg Oncol. 1984;7:329-53. No abstract available.

Luton JP, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med. 1990 Apr 26;322(17):1195-201.

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

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