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

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00071058
First received: October 9, 2003
Last updated: September 12, 2012
Last verified: September 2012
  Purpose

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.

Condition Intervention Phase
Adrenal Cortex Neoplasms
Drug: XR9576 (Tariquidar)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Percentage of Participants With a Partial or Complete Response [ Time Frame: Every 6 weeks for up to a year ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Number of Participants With Adverse Events [ Time Frame: 60 months, 19 days ] [ Designated as safety issue: Yes ]
    Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.


Enrollment: 50
Study Start Date: October 2003
Study Completion Date: November 2009
Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Surgery plus chemotherapy

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)
Other Name: 150 mg tariquidar through central venous catheter over 30 minutes on days 1 and 3.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00071058

Locations
United States, Maryland
National Cancer Institute (NCI)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Antonio Fojo, M.D. National Cancer Institute, National Institutes of Health
  More Information

Additional Information:
Publications:
Responsible Party: Antonio Fojo, M.D./National Cancer Institute, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00071058     History of Changes
Obsolete Identifiers: NCT00073996
Other Study ID Numbers: 040011, 04-C-0011
Study First Received: October 9, 2003
Results First Received: August 13, 2012
Last Updated: September 12, 2012
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
P-glycoprotein Inhibition
Drug Resistance Reversal
Pharmacodynamics
Molecular Target
Endocrine Cancer
Adrenocortical Cancer
ACC
Adrenocortical Tumor

Additional relevant MeSH terms:
Adrenocortical Carcinoma
Adrenal Cortex Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adrenal Gland Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Adrenal Cortex Diseases
Adrenal Gland Diseases
Endocrine System Diseases
Doxorubicin
Liposomal doxorubicin
Etoposide
Vincristine
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators

ClinicalTrials.gov processed this record on September 29, 2014