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
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
Background:

 Zotiraciclib (TG02) is an investigational drug that penetrates the blood-brain barrier and
 might treat brain tumors. Temozolomide (TMZ) is a drug used to treat brain tumors.

 Objective:

 To find out if Zotiraciclib (TG02) is safe, and to find out if it in combination with TMZ is
 as effective as TMZ alone in people with brain tumors.

 Eligibility:

 People ages 18 and older with a brain tumor that has progressed after standard treatment

 Design:

 In phase I part, the Bayesian optimal interval (BOIN) design will be used to find the MTD of
 Zotiraciclib (TG02) for Arm 1 (dose dense TMZ) and Arm 2 (metronomic TMZ) independently.

 In Phase II part, a Bayesian design based on posterior probability will be used to monitor
 eficacy.

 Participants will be screened with:

 -  Medical history

 -  Physical exam

 -  Blood and urine tests

 -  MRI of the brain if they have not had one in 14 days

 -  Heart test

 -  Tissue sample from prior surgeries

 Participants will take Zotiraciclib (TG02) plus TMZ by mouth in 28-day cycles.

 -  Some will take TMZ for 7 days on and 7 days off. Others will take it every day.

 -  They will all take Zotiraciclib (TG02) three days before Cycle 1, and then on four days
 during every cycle.

 -  They will all get treatment to prevent vomiting and diarrhea before and for 24 hours
 after each Zotiraciclib (TG02) dose.

 -  They will all keep a diary of when they take the drugs and their symptoms.

 Participants will have study visits. These include:

 -  Physical exam, heart test, quality of life questionnaire, brain MRI, and urine tests
 every 4 weeks

 -  Blood tests every 2 weeks

 Participants will continue treatment until their disease gets worse or they have intolerable
 side effects.

 Participants will also be enrolled in another protocol to test molecular markers for their
 brain tumor.
Background:

 -  Zotiraciclib (TG02) is a pyrimidine-based multi-kinase inhibitor that has been shown to
 have inhibitory effects on CDKs, Janus Kinase 2 (JAK2) and Fm-like tyrosine kinase 3
 (Flt3). It is orally administered and penetrates blood brain barrier (BBB). There is
 clinical experience in using Zotiraciclib (TG02) as both a single agent and in
 combination with other chemotherapy agents for cancer treatment.

 -  Temozolomide (TMZ) is an oral alkylating agent that has proven efficacy in anaplastic
 glioma and glioblastoma. It was approved by the U.S. Food and Drug Administration (FDA)
 to treat anaplastic astrocytoma and glioblastoma in adults. Both a dose-dense (dd)
 schedule, 7 days on and 7 days off and a metronomic (mn) daily dosing schedule have been
 used to treat recurrent high-grade gliomas.

 -  Our preclinical data have demonstrated that Zotiraciclib (TG02) down-regulates CDK9
 activity and its target proteins, such as anti-apoptotic protein Mcl-1, XIAP and
 survivin. A treatment with Zotiraciclib (TG02) and TMZ has synergistic anti-glioma
 effects in a variety of glioma models with different genetic background. This serves as
 the basis for this proposed clinical trial.

 Objectives:

 Phase I:

 -To determine the maximum tolerated dose (MTD) of Zotiraciclib (TG02) plus TMZ using both the
 dd and mn TMZ schedules in adult patients with recurrent anaplastic astrocytoma or
 glioblastoma/gliosarcoma.

 Phase II:

 -To determine the efficacy of Zotiraciclib (TG02) plus TMZ versus TMZ alone in patients with
 recurrent WHO grade III or IV astrocytoma as determined by progression free survival.

 Eligibility:

 -  Documented pathology diagnosis of anaplastic astrocytoma [WHO grade III], or
 glioblastoma/gliosarcoma (WHO grade IV) with recurrent disease. If the pathology
 diagnosis is anaplastic glioma or anaplastic oligoastrocytoma, evidence of either intact
 1p/19q chromosomes or molecular features suggesting astrocytic tumor must be present.
 (including, but not limited to ATRX and/or TP53 mutation)

 -  No prior use of bevacizumab as a treatment for brain tumor.

 -  No more than two prior relapses for Phase I and no more than one prior relapse for Phase
 II.

 -  Patients must have recurrent disease, either histologically proven or with imaging
 suggestive of recurrent disease

 -  Tumor tissues available for review to confirm the histologic diagnosis.

 -  Tumor tissue blocks available for molecular profiling analysis.

 Design:

 -  Phase I:

 -  This portion of the study is conducted in two stages: The MTD finding and cohort
 extension. Two treatment arms and several dose levels are planned.

 -  In the MTD finding part, TMZ with two alternate schedules (dd and mn) in
 combination with Zotiraciclib (TG02) will be administered.

 -  A cohort extension of both arms will be performed at each MTD and the treatment arm
 with a better progression free survival at 4 months (PFS4) will be selected for the
 combination treatment arm for Phase II.

 -  Pharmacokinetic, pharmacogenetic studies and neutrophil analysis will be performed
 during the cohort extension of both arms.

 -  A maximum of 72 patients will be enrolled to this component for the trial.

 -  Phase II:

 -  Patients will be randomized between two competing treatment arms: ("winner" of dd
 vs mn) TMZ + Zotiraciclib (TG02) versus dd/mn TMZ alone using a Bayesian clinical
 trial design. The dosage for the combination arm will be derived from the MTD
 determined in the Phase I

 component of the study.

 -  The treatment schedule will be identical to that described above in the phase I
 component, with each cycle comprising 28 days.

 -  Patients will continue treatment until tumor progression or unacceptable toxicity
 occurs.

 -  At progression, patients randomized to the control arm (Temozolomide [TMZ] alone) will
 be offered the opportunity to continue TMZ and additional treatment with Zotiraciclib
 (TG02).
-  INCLUSION CRITERIA:

 -  Inclusion criteria are same in both Phase I and Phase II parts, except for the number
 of prior disease relapses

 -  Patients must have pathologic diagnosis of anaplastic astrocytoma defined as WHO grade
 III or glioblastoma/gliosarcoma, WHO grade IV, which are confirmed by NCI Laboratory
 of Pathology. If the pathology diagnosis is anaplastic glioma or anaplastic
 oligoastrocytoma, evidence of either intact 1p/19q chromosomes or molecular features
 suggesting astrocytic tumor must be present.

 (including, but not limited to ATRX, TP53).

 -  Patients must have recurrent disease, histologically proven or imaging suggestive of
 recurrent disease as determined by 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 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 (ANC > 1,500/mm3, platelet count of >
 100,000/mm3), adequate liver function (ALT and AST< 3 times upper limit normal and
 alkaline phosphatase < 2 times upper limit normal, total bilirubin < 1.5mg/dl), and
 adequate renal function (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 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 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 PET scan) in which case the
 principal investigator s discretion may determine appropriate timepoint at which study
 therapy may begin.

 -  Women of childbearing potential must have a negative beta-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 NOB Natural History protocol to allow the
 assessment of molecular tumor markers.

 EXCLUSION CRITERIA:

 -  Patients who are receiving any other investigational agents. However, prior enrollment
 on a study using investigational agents is acceptable

 -  Patients with prior bevacizumab use for tumor treatment. Patients who received
 bevacizumab for symptom management, including but not limited to cerebral edema,
 pseudoprogression can be included in the study(To date, there have been no effective
 regimens developed for recurrent malignant gliomas that are refractory to bevacizumab.
 Inclusion of this patient population may impact the ability to determine the efficacy
 of Zotiraciclib (TG02) with TMZ.)

 -  Any serious medical condition, laboratory abnormality, or psychiatric illness that
 would prevent the subject from providing informed consent.

 -  Any condition, including the presence of clinically significant laboratory
 abnormalities, which places the patient at unacceptable risk if he/she were to
 participate 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 HIV or
 Hepatitis C infection, because these patients are at increased risk of lethal
 infections when treated with marrow-suppressive therapy.

 -  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 biologic
 composition to temozolomide and/or Zotiraciclib (TG02).

 -  Patients with a history of any other cancer (except non-melanoma skin cancer or
 melanoma in-situ following curative surgical resection; or carcinoma in-situ of the
 cervix or bladder), unless in complete remission and off all therapy for that disease
 for a minimum of 3 years, are ineligible.

 -  Zotiraciclib (TG02) is primarily metabolized by CYP1A2 and CYP3A4. Patients receiving
 any medications or substances that are strong inhibitors or inducers of CYP1A2 and/or
 CYP3A4 are ineligible.

 -  Patients, who continue to have prolonged QTc (males: greater than 450ms; females:
 greater than 470ms as calculated by Fridericia s correction formula) despite normal
 electrolyte balance and discontinuation of medications known to prolong QTc, will be
 excluded from the study.