Surgery Plus Chemotherapy (Doxorubicin, Vincristine and Etoposide), Mitotane, and Tariquidar to Treat Adrenocortical Cancer
Condition: Adrenal Cortex Neoplasms
MeSH terms: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma
Intervention: XR9576 (Tariquidar)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: P-glycoprotein Inhibition; Drug Resistance Reversal; Pharmacodynamics; Molecular Target; Endocrine Cancer; Adrenocortical Cancer; ACC; Adrenocortical Tumor

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.
    

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 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.