Trial Information

Combination of Hydroxyurea and Verapamil for Refractory Meningiomas

The investigators have demonstrated previously that the calcium channel antagonists (CCAs)
verapamil, nifedipine, and diltiazem can block in vitro and in vivo meningioma growth at
clinically relevant doses (Jensen, Lee et al. 1995; Jensen, Petr et al. 2000; Jensen and
Wurster 2001). However, only modest growth inhibition was exhibited in the tumors in these
studies with CCAs alone. Many authors have shown augmented growth inhibition by adding CCAs
to traditional chemotherapies in other tumor types (Tsuruo, Iida et al. 1981; Tsuruo, Iida
et al. 1983; Helson 1984; Robinson, Clutterbuck et al. 1985; Ince, Appleton et al. 1986;
Merry, Fetherston et al. 1986; Cano-Gauci and Riordan 1987). For instance, the combination
of verapamil and 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) is better than BCNU alone in
inhibiting the growth of human gliomas in vitro and in vivo (Bowles, Pantazis et al. 1990).
Calcium antagonists seem to exert the majority of their anti-tumor effects by inhibiting
calcium dependent secondary messenger systems (Metcalfe, 1986 #74; Jensen, 2000 #15).
Furthermore, the investigators have more recently demonstrated that the addition of a
verapamil or diltiazem with HU enhances the growth inhibition seen with these drugs in vitro
and in vivo.

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.

Hydroxyurea is well absorbed after oral administration with the peak serum concentration
achieved in two hours. The drug is excreted primarily in the urine, either as urea or as the
unchanged compound. The drug is supplied as 500 mg capsules in a white crystalline powder.
It is stored at room temperature. Dosing is usually in the range of 20 mg/kg/day with
adjustments necessary for patients with renal insufficiency. In the current study population
patients would be usually treated with 500mg twice a day. It is contraindicated in patients
with myelosuppression or severe anemia.

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. It is contraindicated in patients with left ventricular
dysfunction, congestive hart failure, hypotension (systolic <90bpm) 2nd or 3rd degree
atrioventricular block (except in patients with a functioning artificial pacemakers), or
sick sinus syndrome and atrial flutter or atrial fibrillation and an accessory bypass tract
(Wolff-Parkinson-White Syndrome, Lown-Ganong-Levine Syndrome). Serious adverse reactions
associated with Verapamil use are congestive heart failure, hypotension, bradycardia, 2nd or
3rd degree AC block, angina, myocardial infarction, syncope and GI obstruction.

STUDY PROCEDURES:

Screening and pretreatment assessments: Written informed consent is obtained before
study-specific screening evaluations are performed. After receiving a subject's agreement to
participate in the study and verifying that the subject meets eligibility criteria, the
following will be performed: Medical and surgical history, prior cancer therapy (including
prior chemotherapy and radiation therapy), complete physical examination, orthostatic vital
signs, blood pressure, heart rate, temperature, weight, height, Karnofsky performance status
(See appendix), neurological evaluation, current medications, and drug allergies. The
following laboratory evaluations will be obtained: complete blood count (including
differential, hemoglobin, and platelet count), serum chemistries (BUN, creatine, sodium,
potassium, bicarbonate, chloride, calcium, glucose, LDH, total protein, total bilirubin,
ALT, AST, alkaline phosphatase, albumin), serum pregnancy test (for woman of childbearing
age, for all other women - documentation in the medical history will confirm that the
subject is not of childbearing potential). All subjects will undergo an ECG test at
screening. Patients with incomplete bundle branch or first degree AV conductions problems
that don't exclude them from the study will be monitored with serial monthly ECG exams or
more frequently if symptoms occur. All subjects will undergo an MRI of the brain (or CT with
contrast if unable to do MRI) with and without Gadolinium contrast to assess tumor
measurements within three to four weeks prior to beginning treatment. Patients will also
undergo Positron Emission Tomography (PET) with metabolic FDG (radiopharmaceutical
fluorodeoxyglucose) markers to assess tumor activity. Baseline FDG/PET scans will be given
to all enrolled patients at screening and every 6 months, thereafter.

Assessments during treatment phase: Patients receive oral hydroxyurea twice daily for 2
years in the absence of disease progression or unacceptable toxicity. Responders may
continue beyond the 2 years of protocol treatment at the discretion of the physician. If the
therapy is stopped for any reason, therapy may be reinstituted if the discontinuance does
not exceed 4 consecutive weeks. The dose is 20 mg/kg/day divided in twice daily doses. The
calculated dose will be rounded up or down to the nearest multiple of 500 mg. Patients will
typically receive either 1,000 mg/day or 1,500 mg/day. If the dose is 1,500 mg/day, it
should be divided as 500 mg po every morning and 1,000 mg po. at bedtime. Verapamil
sustained release tablets will begin at a dose of 120 mg each day for two weeks, then 240 mg
each day for two weeks, then 360 mg each day for two weeks, then 240 mg twice a day. If the
baseline SBP is <110 mmHg then the initial Verapamil sustained release dose will be 60 mg
(1/2 of a 120 mg tablet) each day for two weeks. Patients will have blood pressure and heart
rate measurements done weekly for the first month and them monthly thereafter. Other
clinical and laboratory evaluations will be performed at 1 month intervals and include:
limited physical examination, orthostatic vital signs, blood pressure, heart rate,
temperature, Karnofsky performance status, neurologic evaluation, serum chemistries (BUN,
creatine, sodium, potassium, bicarbonate, chloride, calcium, glucose, LDH, total protein,
total bilirubin, ALT, AST, alkaline phosphatase, albumin). Concomitant medications and
adverse events will also be collected. Complete blood counts (including differential,
hemoglobin, and platelet count), will be done weekly throughout the study until counts
stabilize for two months, and then labs will be done every two weeks thereafter to closely
monitor the side-effect of myelosuppression.

Patients with incomplete bundle branch or first degree AV conduction abnormalities that
don't exclude them from the study will be monitored with monthly ECG exams or more
frequently if symptoms occur. Subjects will undergo MRI with gadolinium (or CT with contrast
if unable to do MRI) every three months after beginning treatment. Measurements will be made
of the image slice with the largest cross sectional area. Two orthogonal measures will be
made to determine maximal AP and lateral dimensions. PET imaging will be done at baseline
and every 6 months and proliferative and metabolic activity will be compared to baseline
images. Tumor location and tumor size will be obtained by CT/MRI. Treatment response and
clinical progression can frequently be difficult to measure directly. Serial neurological
exams, CT/MRI and PET scans may provide a guide to the actual course of response and
progression. Deterioration in neurological status and tumor regrowth on CT/MRI and PET must
be sustained over time to declare clinical progression. The time interval until progression
will be measured from the day of last CT/MRI before treatment and every 3-4 months until
deterioration is documented. The patient should consistently be followed with the same
diagnostic imaging study and formal evaluation of radiological tumor progression and tumor
response will be done post study

Patients will be treated for up to two years on the study. Progression of disease will be
defined as a greater than 25% increase of largest cross sectional area by two orthogonal
measurements. Patients will be discontinued for illness that prevents further treatment
including unacceptable toxicity (Grade 3 or 4 that fails to resolve with dose medication per
protocol) of study drugs.