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

Background:

- 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 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 TG02 down-regulates CDK9 activity and its
target proteins, such as anti-apoptotic protein Mcl-1, XIAP and survivin. A treatment
with 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 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 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 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 + 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 (TMZ alone) will be offered the
opportunity to continue TMZ and additional treatment with 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, a MRI should be
done no later than 96 hours in the immediate post-operative period or at least
within 4 weeks postoperatively, 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 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 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 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 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 TG02.

- Patients with a history of any other cancer (except non-melanoma skin cancer 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.

- 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.