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

Adrenocortical cancer (ACC) is a rare tumor that is optimally treated with surgical resection. However, many patients present with unresectable disease and relapses are common after surgical resection creating a need for more effective systemic therapies. Several investigators have reported responses to a variety of chemotherapy agents, without a clear improvement in overall survival. A possible explanation for these disappointing results is the high levels of expression of P-glycoprotein (Pgp) seen in a majority of adrenocortical cancers. Pgp, a membrane protein that can function as a drug efflux pump lowering the intracellular concentrations of various drugs, has been implicated as a mechanism of drug resistance.

A prior National Cancer Institute (NCI) study (referred to as MAVE) tried to improve response rates by using a combined modality approach with chemotherapy and surgery. Prior in vitro studies had shown that mitotane inhibited Pgp and that continuous exposure to doxorubicin and vincristine was more effective at overcoming Pgp-mediated resistance than the same drugs given on an intermittent schedule. The MAVE study used daily oral mitotane with infusional doxorubicin, vincristine, and etoposide prior to tumor resection in patients with resectable or potentially resectable tumors. The results showed an overall response rate of 19% (including minor responses), and an overall median survival of 13.5 months. These results were similar to those reported with previous regimens in adrenocortical cancer (ACC). A possible explanation for the failure to achieve a higher response rate may be that mitotane was unable to inhibit Pgp. Although the serum levels of mitotane achieved in patients had been shown to block Pgp in vitro, inhibition of Pgp in patients was not accomplished, as documented by a validated surrogate assay using Pgp-expressing CD56+ cells and the Pgp substrate, rhodamine. Thus the question of whether Pgp inhibition would improve response rates remains unanswered.

This trial will attempt to answer the latter question by using an agent, tariquidar (XR9576), which has been proven to inhibit Pgp in humans with minimal toxicity alone or in combination with chemotherapy. Tariquidar will be used with the regimen from the prior MAVE study in an effort to improve response rates and overall survival in patients with ACC whose options at this time are limited.

• 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 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.

Ability and willingness to follow the guidelines of the clinical protocol including visits to National Cancer Institute (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 multi-gated acquisition scan (MUGA), echocardiogram (Echo), or cardiac magnetic resonance imaging (MRI) in patients with a clinical history suggestive of systolic dysfunction.