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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

Phase 2
18 Years
Not Enrolling
Adrenal Cortex Neoplasms

Thank you

Trial Information

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

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

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.


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.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Percentage of Participants With a Partial or Complete Response

Outcome Description:

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.

Outcome Time Frame:

Every 6 weeks for up to a year

Safety Issue:


Principal Investigator

Antonio Fojo, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

October 2003

Completion Date:

November 2009

Related Keywords:

  • Adrenal Cortex Neoplasms
  • P-glycoprotein Inhibition
  • Drug Resistance Reversal
  • Pharmacodynamics
  • Molecular Target
  • Endocrine Cancer
  • Adrenocortical Cancer
  • ACC
  • Adrenocortical Tumor
  • Adrenal Cortex Neoplasms
  • Neoplasms
  • Adrenocortical Carcinoma



National Cancer Institute (NCI) Bethesda, Maryland  20892