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

• •Patients must have pathologic diagnosis of anaplastic astrocytoma defined as World Health Organization (WHO) grade III or glioblastoma/gliosarcoma, WHO grade IV, which are confirmed by National Cancer Institute (NCI) Laboratory of Pathology. If the pathology diagnosis is anaplastic glioma or anaplastic oligoastrocytoma, evidence of either intact combined loss of the short arm chromosome 1 (i.e. 1p) and the long arm of chromosome 19 (1p/19q) chromosomes or molecular features suggesting astrocytic tumor must be present (including, but not limited to alpha-thalassemia/mental retardation, alpha-thalassemia/mental retardation, X-linked (ATRX), tumor protein P53 (TP53).
• •Patients must have recurrent disease, histologically proven or imaging suggestive of recurrent disease as determined by principal investigator (PI). Prior implantation of Gliadel wafers is acceptable, if tumor recurrence is confirmed by histologic examination of the recurrent tumor
• •Patients must have the ability to understand and the willingness to sign a written informed 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 the study and no more than one prior relapse to be eligible for phase II.
• •Patients must have undergone prior standard therapy for their primary disease. For patients with glioblastoma, this would include surgical resection, or biopsy, if safe resection was not permitted due to the tumor location, radiation and adjuvant temozolomide. For patients with anaplastic astrocytoma, this would include surgical resection, radiation and adjuvant chemotherapy procarbazine, lomustine (CCNU) and vincristine (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 (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)\< 3 times upper limit normal and alkaline phosphatase \< 2 times upper limit normal, total bilirubin \< 1.5mg/dl), and adequate renal function (blood urea nitrogen (BUN) \< 1.5 times institutional normal and serum creatinine \< 1.5 mg/dl) prior to registration. These tests must be performed within 14 days prior to registration. Total bilirubin: patients with Gilbert's Syndrome are eligible for the study. (Total bilirubin level can be exempted from the eligibility criterion.)
• •Patients must have recovered from the toxic effects of prior therapy to less than grade 2 toxicity per Common Terminology Criteria (CTC) version 4 (except deep vein thrombosis)
• •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 does not count.
• •Patients having undergone recent resection of recurrent or progressive tumor will be eligible given all of the following conditions apply:
• •* At least 2 weeks (14 days) have elapsed from the date of surgery and the patients have recovered from the effects of surgery.
• •* Evaluable or measureable disease following resection of recurrent malignant glioma is not mandated for eligibility into the study.
• •* To best assess the extent of residual disease post-operatively, an magnetic resonance imaging (MRI) should be done no later than 96 hours in the immediate post-operative period or at least within 4 weeks post- operatively, within 14 days prior to registration. If the 96-hour scan is more than 14 days before registration, the scan needs to be repeated. The patient must have been on a stable steroid dose for at least 5 days prior to the baseline MRI. Steroids may be initiated as clinically indicated once baseline imaging has been completed with a goal of titrating steroids as soon as clinically warranted.
• •Patients must have received prior radiation therapy and must have an interval of greater than or equal to 12 weeks (84 days) from the completion of radiation therapy to study entry except if there is unequivocal evidence for tumor recurrence (such as histological confirmation or advanced imaging data such as positron emission tomography (PET) scan) in which case the principal investigators discretion may determine 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 of Zotiraciclib (TG02) on the developing human fetus are unknown. For this reason, women of childbearing potential must not be pregnant, must not be breast-feeding, and must practice adequate contraception for the duration of the study, and for 30 days after the last dose of study medication.
• •Male patients on treatment with Zotiraciclib (TG02) must agree to use an adequate method of contraception for the duration of the study, and for 30 days after the last dose of study medication as the effects of Zotiraciclib (TG02) on the developing human fetus are unknown.
• •Patients must agree to enroll on the Neuro-oncology Branch (NOB) Natural History protocol to allow the assessment of molecular tumor markers.