Combination of Hydroxyurea and Verapamil for Refractory Meningiomas
|First Received Date ICMJE||June 26, 2008|
|Last Updated Date||July 23, 2013|
|Start Date ICMJE||December 2007|
|Estimated Primary Completion Date||June 2014 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||To determine the safety of the combination of hydroxyurea and verapamil for treatment of patients with progressive, recurrent meningiomas. To characterize the toxicity of this drug combination. [ Time Frame: December 2011 ] [ Designated as safety issue: Yes ]|
|Original Primary Outcome Measures ICMJE
||• To determine the safety of the combination of hydroxyurea and verapamil for treatment of patients with progressive, recurrent meningiomas. To characterize the toxicity of this drug combination. [ Time Frame: December 2010 ] [ Designated as safety issue: Yes ]|
|Change History||Complete list of historical versions of study NCT00706810 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||To determine the objective response rate of patients treated with this drug combination by magnetic resonance imaging and metabolic PET imaging. • To determine the 12 month and 24 month progression-free survival rates of the treatment population [ Time Frame: December 2011 ] [ Designated as safety issue: No ]|
|Original Secondary Outcome Measures ICMJE
||• To determine the objective response rate of patients treated with this drug combination by magnetic resonance imaging and metabolic PET imaging. • To determine the 12 month and 24 month progression-free survival rates of the treatment population [ Time Frame: December 2010 ] [ Designated as safety issue: No ]|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Combination of Hydroxyurea and Verapamil for Refractory Meningiomas|
|Official Title ICMJE||Combination of Hydroxyurea and Verapamil for Refractory Meningiomas|
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).
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.
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Study Arm (s)||Experimental: All participants
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Estimated Enrollment ICMJE||18|
|Estimated Completion Date||June 2014|
|Estimated Primary Completion Date||June 2014 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||United States|
|NCT Number ICMJE||NCT00706810|
|Other Study ID Numbers ICMJE||HCI25089|
|Has Data Monitoring Committee||Yes|
|Responsible Party||University of Utah|
|Study Sponsor ICMJE||University of Utah|
|Collaborators ICMJE||Not Provided|
|Information Provided By||University of Utah|
|Verification Date||July 2013|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP