Zotiraciclib (TG02) Plus Dose-Dense or Metronomic Temozolomide Followed by Randomized Phase II Trial of Zotiraciclib (TG02) Plus Temozolomide Versus Temozolomide Alone in Adults With Recurrent Anaplastic Astrocytoma and Glioblastoma

• INCLUSION CRITERIA:
• Inclusion criteria are same in both Phase I and Phase II parts, except for the numberof prior disease relapses
• Patients must have pathologic diagnosis of anaplastic astrocytoma defined as WorldHealth Organization (WHO) grade III or glioblastoma/gliosarcoma, WHO grade IV, whichare confirmed by National Cancer Institute (NCI) Laboratory of Pathology. If thepathology diagnosis is anaplastic glioma or anaplastic oligoastrocytoma, evidence ofeither intact combined loss of the short arm chromosome 1 (i.e. 1p) and the long armof chromosome 19 (1p/19q) chromosomes or molecular features suggesting astrocytictumor must be present (including, but not limited to alpha-thalassemia/mentalretardation, alpha-thalassemia/mental retardation, X-linked (ATRX), tumor protein P53 (TP53).
• Patients must have recurrent disease, histologically proven or imaging suggestive ofrecurrent disease as determined by principal investigator (PI). Prior implantation ofGliadel wafers is acceptable, if tumor recurrence is confirmed by histologicexamination of the recurrent tumor
• Patients must have the ability to understand and the willingness to sign a writteninformed consent document.
• Patients must be greater than or equal to 18 years old.
• No more than two prior disease relapses to be eligible for the phase I portion of thestudy and no more than one prior relapse to be eligible for phase II.
• Patients must have undergone prior standard therapy for their primary disease. Forpatients with glioblastoma, this would include surgical resection, or biopsy, if saferesection was not permitted due to the tumor location, radiation and adjuvanttemozolomide. For patients with anaplastic astrocytoma, this would include surgicalresection, radiation and adjuvant chemotherapy procarbazine, lomustine (CCNU) andvincristine (PCV) or temozolomide.
• Tumor tissue must be available for review to confirm histological diagnosis.
• Tumor block or unstained slides must be available for molecular profiling.
• Karnofsky > 60 percent
• Patients must have adequate bone marrow function (absolute neutrophil count (ANC) > 1,500/mm^3, platelet count of > 100,000/mm^3), adequate liver function (alanineaminotransferase (ALT) and aspartate aminotransferase (AST)< 3 times upper limitnormal and alkaline phosphatase < 2 times upper limit normal, total bilirubin < 1.5mg/dl), and adequate renal function (blood urea nitrogen (BUN) < 1.5 timesinstitutional normal and serum creatinine < 1.5 mg/dl) prior to registration. Thesetests must be performed within 14 days prior to registration. Total bilirubin:patients with Gilbert's Syndrome are eligible for the study. (Total bilirubin levelcan be exempted from the eligibility criterion.)
• Patients must have recovered from the toxic effects of prior therapy to less thangrade 2 toxicity per Common Terminology Criteria (CTC) version 4 (except deep veinthrombosis)
• At the time of registration, subject must be removed from prior therapy as follows:
• greater than or equal to (28 days) from any investigational agent,
• greater than or equal to 4 weeks (28 days) from prior cytotoxic therapy,
• greater than or equal to 2 weeks (14 days) from vincristine,
• greater than or equal to 6 weeks (42 days) from nitrosoureas,
• greater than or equal to 3 weeks (21 days) from procarbazine administration,
• greater than or equal to 1 week (7 days) for non-cytotoxic agents, e.g.,interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. radiosensitizer doesnot count.
• Patients having undergone recent resection of recurrent or progressive tumor will beeligible given all of the following conditions apply:
• At least 2 weeks (14 days) have elapsed from the date of surgery and the patientshave recovered from the effects of surgery.
• Evaluable or measureable disease following resection of recurrent malignantglioma is not mandated for eligibility into the study.
• To best assess the extent of residual disease post-operatively, an magneticresonance imaging (MRI) should be done no later than 96 hours in the immediatepost-operative period or at least within 4 weeks post- operatively, within 14days prior to registration. If the 96-hour scan is more than 14 days beforeregistration, the scan needs to be repeated. The patient must have been on astable steroid dose for at least 5 days prior to the baseline MRI. Steroids maybe initiated as clinically indicated once baseline imaging has been completedwith a goal of titrating steroids as soon as clinically warranted.
• Patients must have received prior radiation therapy and must have an interval ofgreater than or equal to 12 weeks (84 days) from the completion of radiation therapyto study entry except if there is unequivocal evidence for tumor recurrence (such ashistological confirmation or advanced imaging data such as positron emissiontomography (PET) scan) in which case the principal investigators discretion maydetermine appropriate timepoint at which study therapy may begin.
• Women of childbearing potential must have a negative beta-human chorionic gonadotropin (HCG) pregnancy test documented within 14 days prior to registration. The effects ofZotiraciclib (TG02) on the developing human fetus are unknown. For this reason, womenof childbearing potential must not be pregnant, must not be breast-feeding, and mustpractice adequate contraception for the duration of the study, and for 30 days afterthe last dose of study medication.
• Male patients on treatment with Zotiraciclib (TG02) must agree to use an adequatemethod of contraception for the duration of the study, and for 30 days after the lastdose of study medication as the effects of Zotiraciclib (TG02) on the developing humanfetus are unknown.
• Patients must agree to enroll on the Neuro-oncology Branch (NOB) Natural Historyprotocol to allow the assessment of molecular tumor markers.

EXCLUSION CRITERIA:

• Patients who are receiving any other investigational agents. However, prior enrollmenton a study using investigational agents is acceptable
• Patients with prior bevacizumab use for tumor treatment. Patients who receivedbevacizumab for symptom management, including but not limited to cerebral edema,pseudoprogression can be included in the study (To date, there have been no effectiveregimens developed for recurrent malignant gliomas that are refractory to bevacizumab.Inclusion of this patient population may impact the ability to determine the efficacyof Zotiraciclib (TG02) with Temozolomide (TMZ.)
• Any serious medical condition, laboratory abnormality, or psychiatric illness thatwould prevent the subject from providing informed consent.
• Any condition, including the presence of clinically significant laboratoryabnormalities, which places the patient at unacceptable risk if he/she were toparticipate in the study or confounds the ability to interpret data from the study.These would include:
• Active infection (including persistent fever) including known history of humanimmunodeficiency virus (HIV) or Hepatitis C infection, because these patients areat increased risk of lethal infections when treated with marrow-suppressivetherapy.
• Diseases or conditions that obscure toxicity or dangerously alter drug metabolism
• Serious concurrent medical illness e.g. symptomatic congestive heart failure
• History of allergic reactions attributed to compounds of similar chemical or biologiccomposition to temozolomide and/or Zotiraciclib (TG02).
• Patients with a history of any other cancer (except non-melanoma skin cancer ormelanoma in-situ following curative surgical resection; or carcinoma in-situ of thecervix or bladder), unless in complete remission and off all therapy for that diseasefor a minimum of 3 years, are ineligible.
• Zotiraciclib (TG02) is primarily metabolized by Cytochrome P450 1A2 (CYP1A2) andCytochrome P450 3A4 (CYP3A4). Patients receiving any medications or substances thatare strong inhibitors or inducers of CYP1A2 and/or CYP3A4 are ineligible.
• Patients, who continue to have prolonged corrected QT interval (QTc) (males: greaterthan 450ms; females: greater than 470ms as calculated by Fridericia s correctionformula) despite normal electrolyte balance and discontinuation of medications knownto prolong QTc, will be excluded from the study.