Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer
Condition: Adrenal Cortex Neoplasms
MeSH terms: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma
Intervention: Axitinib
Intervention description: 5 mg tab orally twice a day with food every 28 days
Intervention MeSH terms: Axitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Selective VEGF Inhibitor; Clinical Activity; Response Rate; Measurable Disease; Biological Markers; Adrenocortical Cancer

Summary:

      Background:

      - Adrenocortical carcinoma is an aggressive cancer that starts in the adrenal gland at the
      top of the kidneys. It has a low survival rate if standard treatment options are not
      effective. Axitinib is an experimental drug that is being studied to determine if it can stop
      tumors from growing or make them smaller. Researchers are interested in investigating
      axitinib in individuals with aggressive or otherwise untreatable adrenocortical cancer.

      Objectives:

      - To evaluate the effectiveness of axitinib in individuals who have adrenocortical cancer
      that is inoperable and has not responded to standard treatments.

      Eligibility:

      - Individuals at least 18 years of age who have been diagnosed with adrenocortical cancer
      that has not responded to standard treatments.

      Design:

        -  Participants will be screened with a full physical examination and medical history, as
           well as tumor imaging studies.

        -  Participants may have a tumor biopsy prior to starting axitinib.

        -  All participants will receive axitinib to take twice a day with food for 28 days (1
           cycle). Participants should not drink grapefruit juice or smoke cigarettes while
           participating in this study.

        -  After the first cycle, the dose may be increased and additional cycles will be given if
           the treatment has not had serious side effects.

        -  Participants will have regular examinations while taking axitinib, including blood
           samples and tumor imaging studies to determine if the tumor has stopped growing. Blood
           pressure levels will be carefully monitored during treatment to evaluate potential risk
           for high blood pressure.

        -  Participants may have a second tumor biopsy 20 to 30 days after treatment begins.

        -  Treatment will continue as directed by the study researchers.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Pathologic confirmation of adrenocortical cancer by the Laboratory of Pathology,
                  National Cancer Institute (NCI).

               2. Measurable disease at presentation.

               3. A life expectancy of at least 3 months and Eastern Cooperative Oncology Group
                  (ECOG) performance status less than or equal to 2.

               4. Age greater than or equal to 18 years.

               5. Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in
                  the case of nitrosourea) prior to enrollment date; 2 weeks if the last therapy
                  was received as part of a phase 0 or exploratory investigational new drug (IND)
                  trial. Last surgery more than 4 weeks prior to enrollment, to allow for wound
                  healing. Core biopsies or fine needle aspiration (FNA) will not require any
                  waiting period.

               6. 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.

               7. Prior mitotane therapy is allowed. Patients with a history of a functional tumor
                  who are receiving mitotane to control the excess hormone production may continue
                  to receive mitotane.

               8. Organ and marrow function as defined below:

          -  Total bilirubin less than or equal to 1.5 x ULN (upper limit of normal), unless the
             patient meets the criteria for Gilbert's Syndrome. The upper limit value for bilirubin
             for subjects with Gilbert's Syndrome is less than 3 mg/dl.

        Note: A diagnosis of Gilbert's disease will be made in the presence of (1) unconjugated
        hyperbilirubinemia noted on several occasions; (2) normal results from complete blood count
        (CBC) count, reticulocyte count, and blood smear; (3) normal liver function test results;
        and (4) an absence of other disease processes that can explain the unconjugated
        hyperbilirubinemia.

          -  Aspartate aminotransaminase (AST) less than or equal to 2.5 times ULN, alanine
             aminotransaminase (ALT) greater than or equal to 2.5 times ULN

          -  Amylase and lipase equal to, or less than, the institutional 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.

             9. Ability to understand and sign an informed consent document.

             10. Ability and willingness to follow the guidelines of the clinical protocol
             including visits to NCI, Bethesda, Maryland for treatment and follow up visits.

             11. Because the effects of chemotherapy on the developing human fetus are potentially
             harmful, women of childbearing potential and men must agree to use adequate
             contraception (hormonal or barrier methods) before, during the study and for a period
             of 3 months after the last dose of chemotherapy.

        EXCLUSION CRITERIA:

          1. Patients with adrenocortical tumors potentially curable by surgical excision alone as
             determined by the Principal Investigator in discussions with the surgical consultants.

          2. Patients who have large abdominal masses impinging on bowel or pulmonary masses with
             encroached vessels and a potential to bleed will be considered on case by case basis
             after careful consultation with multiple disciplines such as radiologists and surgeons
             with main intent being patient safety.

          3. Unstable hypertension defined as a systolic blood pressure greater than 140 mm Hg or
             diastolic pressure greater than 90 mmHg despite optimal medical management and
             patients who are receiving more than 1 antihypertensive agent at trial entry, (not
             including spironolactone) unless the patient has Cushing's Disease with its associated
             hypertension and is well controlled on medications.

          4. 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 adverse events.

          5. Pregnancy, due to the possible adverse effects on the developing fetus.

          6. Lactating women who are breast-feeding due to the possibility of transmitting axitinib
             to the child.

          7. The presence of a second malignancy, other than a skin cancer 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.

          8. Patients with evidence of a bleeding diathesis.

          9. Phosphorus level equal to, or less than, the institutional lower limits of normal that
             cannot be corrected.

         10. Gastrointestinal abnormalities including:

               1. inability to take oral medications

               2. requirement for intravenous alimentation

               3. prior surgical procedure affecting absorption including total gastric resection

               4. treatment for active peptic ulcer disease in the past 6 months

               5. active gastrointestinal bleeding, unrelated to cancer, as evidenced by
                  hematemesis, hematochezia or melena in the past 3 months without evidence of
                  resolution documented by endoscopy or colonoscopy

               6. malabsorption syndrome

         11. Current use or anticipated need for treatment with drugs that are known potent
             cytochrome P450 3A4 (CYP3A4) inhibitors (i.e., grapefruit juice, verapamil,
             ketoconazole, miconazole, itraconazole, erythromycin, telithromycin, clarithromycin,
             indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir,
             fosamprenavir, and delavirdine).

         12. Current use or anticipated need for treatment with drugs that are known CYP3A4
             inducers (i.e., carbamazepine, Phenobarbital, phenytoin, amobarbital, nevirapine,
             primidone, rifabutin, rifampin, and St. John's wort).

         13. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose
             anticoagulants for maintenance of patency of central venous access devise or
             prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular
             weight heparin is allowed.

         14. Active seizure disorder or evidence of brain metastases, spinal cord compression, or
             carcinomatous meningitis.

         15. Any of the following within 12 months prior to study drug administration: myocardial
             infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic
             congestive heart failure, cerebrovascular accident or transient ischemic attack and 6
             months for deep vein thrombosis or pulmonary embolism.

         16. Other severe acute or chronic medical or psychiatric condition, or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration, or may interfere with the interpretation of study results, and in
             the judgment of the investigator would make the patient inappropriate for entry into
             this study.

         17. Current use of drugs that are known inhibitors or inducers of Breast Cancer Resistance
             Protein (BCRP) and Organic Anion Transporting Polypeptide (OATP)1B1/3 or known to
             affect protein binding should be used with caution and with acknowledgement of the
             principal investigator (PI).