International study in multiple centers studying the effect of hydroxy-urea and temozolomide chemotherapy in patients with a recurrent malignant brain tumor (Glioblastoma)

1. Participants must have histologically or cytologically confirmed glioblastoma multiforme

2. Patients may have had any number of prior therapies for glioblastoma. Patients must be at least 28 days from any investigational agent, 28 days from prior cytotoxic therapy (except 23 days from prior temozolomide, 14 days from vincristine, 42 days from nitrosoureas, 21 days from procarbazine administration), and 7 days for patients who received metronomic chemotherapy or non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.

3. Age ¡Ý18 years. Because no dosing or adverse event data are currently available on the use of hydroxyurea in combination with temozolomide in participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.

4. Karnofsky Performance Status (KPS) ¡Ý60%

5. Participants must have normal organ and marrow function as defined below:

− leukocytes ¡Ý3,000/mcL

− absolute neutrophil count ¡Ý1,500/mcL

− platelets ¡Ý100,000/mcL

− total bilirubin within normal institutional limits

− AST(SGOT)/ALT(SGPT) ¡Ü2.5 ¡Á institutional upper limit of normal

− creatinine below upper limit of normal institutional limits
OR

− creatinine clearance ¡Ý60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

6. Progressive disease on contrast-enhanced brain CT or MRI as defined by RANO Criteria [22], or have documented recurrent glioblastoma on diagnostic biopsy. Patients who have been previously treated with bevacizumab therapy that have T2-weighted or FLAIR MRI sequences considered to be progressive disease by the study investigator but have no contrast-enhancing areas of recurrent disease are eligible.

7. Interval of at least 2 weeks from any prior neurosurgical resection (1 week for intracranial biopsy) to start of study drug; and patient must have adequate wound healing.

8. Interval of at least 12 weeks from prior radiotherapy unless there is either: a) histopathologic confirmation of recurrent tumor, or b) new enhancement on MRI outside of the radiation treatment (RT) field.

9. Because cytotoxic agents such as temozolomide and hydroxyurea are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of temozolomide and hydroxyurea administration.

10. Patients must have archival tumor tissue available for molecular analysis and must be willing to consent for this tissue to be analyzed as part of this study. However, if no archival tumor tissue is available, the patient will not be excluded from the study.

11. Ability to understand and the willingness to sign a written informed consent document.

1. Participants who are receiving any other investigational agents or devices in investigation for glioblastoma.

2. Patients must not have been previously treated with an anti-VEGF inhibitor.

3. History of allergic reactions attributed to compounds of similar chemical composition to temozolomide and/or hydroxyurea.

4. 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.

5. Pregnant women are excluded from this study because hydroxyurea and temozolomide have known 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 hydroxyurea and temozolomide, breastfeeding should be discontinued if the mother is treated with hydroxyurea and temozolomide.

6. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with hydroxyurea. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.

7. Patients with a history of a different malignancy are ineligible except for the following circumstances: if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; patients with treated cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. Patients will not be eligible if they have evidence of other malignancy requiring therapy other than surgery within the last 3 years.

8. Major surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 weeks of start of study drug; or not fully recovered from any side effects of previous procedures.

9. Presence of extra-cranial metastatic disease.