Combination of Hydroxyurea and Verapamil for Refractory Meningiomas
Condition: Cancer; Brain Cancer; Meningioma
MeSH terms: Meningioma; Brain Neoplasms
Intervention: Hydroxyurea; Verapamil
Intervention description: Hydroxyurea inhibits DNA synthesis by inhibition of ribonucleotide diphosphate reductase and is a well-known drug used for the treatment of a number of tumor types including head and neck tumors and chronic myelogenous leukemia. It has also been used as an adjuvant for antiretroviral treatment for patients with HIV and as a treatment for polycythemia vera, essential thrombocythemia and sickle cell disease.; Verapamil is another commonly used medication. It is used for the treatment of angina, hypertension, supraventricular arrhythmias, and migraine prophylaxis. Dosing with standard verapamil is 80-120 mg pox three times a day but the sustained release form can be given 120-480mg once or twice each day.
Intervention MeSH terms: Hydroxyurea; Verapamil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Masking description: Open Label
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cancer; Brain cancer; Meningioma

Summary:

      Meningiomas account for 20% of primary adult brain tumors, occurring at an annual incidence
      of 6 per 100,000 (Louis, Scheithauer et al. 2000). Complete surgical resection is the
      treatment of choice but may not possible when the tumor invades critical structures (e.g.,
      skull base, sagittal sinus) (Mirimanoff, Dosoretz et al. 1985; al-Rodhan and Laws 1990;
      Al-Rodhan and Laws 1991; Newman 1994; De Monte 1995; Levine, Buchanan et al. 1999; Barnett,
      Suh et al. 2000; Ragel and Jensen 2003). Up to 20% of meningiomas exhibit a more aggressive
      phenotype that does not respond to standard therapies (Kyritsis 1996). Adjuvant therapies are
      critical for patients with this subset of meningiomas. Radiation therapy and stereotactic
      radiosurgery are good adjuvant therapies but are limited by radiation neurotoxicity, tumor
      size constraints, and injury to adjacent vascular structures or cranial nerves (Goldsmith,
      Wara et al. 1994; Barnett, Suh et al. 2000; Goldsmith and Larson 2000). Standard
      chemotherapeutic treatments have been disappointing (Kyritsis 1996). Even drugs like
      temozolomide that have shown efficacy against malignant brain tumors have failed to inhibit
      the growth of refractory meningiomas in a phase II study (Chamberlain, Tsao-Wei et al. 2004).
    

Eligibility criteria:

        1. Must be age > 18 years

          2. Patient able to provide written informed consent

          3. Histologically confirmed meningioma of any WHO grade (written pathology report from
             surgery required)

          4. Radiographic demonstration of at least 25% increase in tumor cross sectional area
             measured on CT/MRI within last 6 months

          5. Patients refusing or for which there is no further surgical or radiation therapy
             options

          6. WBC at least 2,500/mm3

          7. Platelet count of at least 100,000/mm3

          8. Hemoglobin > 8.0 g/dL

          9. Renal insufficiency (glomerular filtration rate (GFR) < 60 as estimated by the
             Cockcroft-Gault equation) are ineligible

         10. Hepatic disease (ALT, AST, bilirubin, or alkaline phosphatase > 3 times upper limit of
             normal) or known cirrhosis are ineligible

         11. Clinically significant cardiovascular disease specifically those patients with the
             following conditions are ineligible:

               -  congestive heart failure

               -  known bundle branch or AV conduction problems

               -  2nd or 3rd degree atrioventricular block (except in patients with artificial
                  pacemaker),

               -  sick sinus syndrome

               -  atrial flutter or atrial fibrillation with an accessory bypass tract
                  (Wolff-Parkinson-White Syndrome, Lown-Ganong-Levine Syndrome),

               -  history of myocardial infarction in the past 6 months

               -  currently taking beta-blockers, digoxin, or neuromuscular blocking agents

               -  Bradycardia (resting heart rate < 60 beats per minute)

         12. Hypotension (resting blood pressure < 90 systolic)

         13. Altered neuromuscular transmission (Duchenne Muscular Dystrophy, myasthenia gravis)

         14. Karnofsky performance score 50-100%

         15. Life expectancy more than 6 months

         16. Pregnant or nursing females are ineligible. Fertile patients must use an effective
             contraception

         17. Received prior investigational agents in the past 6 months are ineligible