TKI 258 in Von Hippel-Lindau Syndrome (VHL)
Condition: Von Hippel-Lindau Syndrome
MeSH terms: Von Hippel-Lindau Disease; Syndrome
Intervention: Dovitinib
Intervention description: 500 mg (5 capsules) daily by mouth on Days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle (i.e. 5 days on, 2 days off schedule).
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: VHL; Hemangioblastoma; Tumor of the central nervous system; TKI258

Summary:

      The goal of this clinical research study is to learn if dovitinib can safely be given to
      patients who have VHL with a measurable hemangioblastoma (tumor of the central nervous
      system). The effects of this drug on the disease will also be studied.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have genetically confirmed Von Hippel-Lindau (VHL) disease or patients
             with a clinical diagnosis of VHL.

          2. At least one of the following measurable hemangioblastomas which is undergoing
             surveillance and the patient is not at immediate risk of needing intervention for this
             or other lesions. a.) Brain: asymptomatic hemangioblastoma, > 0.5 cm; b.) Spine:
             asymptomatic hemangioblastoma, > 0.5 cm; c.) Renal: solid mass suspicious for RCC >/=1
             cm or cystic mass >/=1 cm; d.) Pancreas: solid mass >/=1cm and < 3 cm suspicious for
             neuroendocrine tumor; e.) Eye: asymptomatic peripapillary and/or macular
             hemangioblastoma, any size f. Adrenal: Pheochromocytoma greater than 1cm in size.
             NOTE: Biopsy is not required given the known natural history in the setting of a
             positive genetic test.

          3. Allowable prior therapy: a.) Patients having undergone prior therapy for VHL lesions
             may enroll as long as other criteria are met. Previously radiated lesions may not be
             considered as target lesions unless they demonstrate unequivocal evidence of growth;
             b.) Major surgery, chemotherapy or radiation therapy completed > 4 weeks prior to
             starting the study treatment.

          4. Age >/= 18 years. Because no dosing or adverse event data are currently available on
             the use of dovitinib in patients < 18 years of age, children are excluded from this
             study but will be eligible for future pediatric single-agent trials, if applicable

          5. ECOG performance status </= 2

          6. Patients must have normal organ and marrow function as defined below: a.) Serum
             aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum
             alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) </=2.5 x local
             laboratory upper limit of normal (ULN) are due to underlying malignancy; b.) Total
             serum bilirubin </=1.5 x ULN; c.) Absolute neutrophil count (ANC) >/= 1500/mcL; d.)
             Platelets >/=100,000/mcL; e.) Hemoglobin >/= 9.0 g/dL; f.) Serum creatinine < 1.5 x
             ULN; g) WBC >/= 3,000/mcl

          7. Males (that have not been sterilized) and females of childbearing potential (female
             that has not be amenorrheic for at least 1 year or that has not surgically sterilized)
             must agree to use double-barrier birth control or abstinence while on the protocol
             treatment

          8. Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          1. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to starting
             study treatment or those who have not recovered (</= Grade 1 )from adverse events due
             to agents administered more than 4 weeks earlier.

          2. Patients may not be receiving any other investigational agents.

          3. Patients with any metastatic disease of any kind.

          4. NCI CTCAE grade 3 hemorrhage within 4 weeks of starting the study treatment.

          5. Any of the following within the 6 months prior to study drug administration:
             myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
             graft, symptomatic congestive heart failure, cerebrovascular accident or transient
             ischemic attack, or pulmonary embolism.

          6. Ongoing cardiac dysrhythmias of NCI CTCAE grade >/= 2.

          7. Prolonged QTc interval on baseline EKG > 470ms.

          8. Hypertension that cannot be controlled by medications (>140/90 mm Hg despite optimal
             medical therapy).

          9. LVEF assessed by 2-D echocardiogram (ECHO) < 50% or lower limit of normal (whichever
             is higher) or multiple gated acquisition scan ( MUGA) < 45% or lower limit of normal
             (whichever is higher).

         10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

         11. Pregnant women are excluded from this study because dovitinib has the potential for
             teratogenic or abortifacient effects. Because there is an unknown but potential risk
             for adverse events in nursing infants secondary to treatment of the mother with
             dovitinib, breastfeeding should be discontinued if the mother is treated with
             dovitinib.

         12. Known HIV-positive patients taking combination antiretroviral therapy are ineligible
             because of the potential for pharmacokinetic interactions with dovitinib. Appropriate
             studies will be undertaken in patients receiving combination antiretroviral therapy
             when indicated.

         13. Women of child-bearing potential, who are biologically able to conceive, not employing
             two forms of highly effective contraception. Highly effective contraception (e.g. male
             condom with spermicide, diaphragm with spermicide, intra-uterine device) must be used
             by both sexes during the study and must be continued for 8 weeks after the end of
             study treatment. Oral, implantable, or injectable contraceptives may be affected by
             cytochrome P450 interactions, and are therefore not considered effective for this
             study. Women of child-bearing potential, defined as sexually mature women who have not
             undergone a hysterectomy or who have not been naturally postmenopausal for at least 12
             consecutive months (e.g., who has had menses any time in the preceding 12 consecutive
             months), must have a negative serum pregnancy test </= 14 days prior to starting study
             treatment.