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Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

dose dense (dd) Temozolomide (TMZ) 125 mg/m\^2 x 7 days on / 7 days off plus Zotiraciclib (TG02) dose escalation

metronomic Temozolomide (TMZ) 50 mg/ m\^2 daily plus Zotiraciclib (TG02) dose escalation

Maximum tolerated dose (MTD) of Zotiraciclib (TG02) from phase I plus and "winner" of dose dense (dd) vs metronomic Temozolomide (TMZ) from phase I

"winner" of dose dense (dd) vs metronomic Temozolomide (TMZ) from phase I alone

Phase I: Two treatment arms and several dose levels are planned; In the maximum tolerated dose (MTD) finding part, Temozolomide (TMZ) with two alternate schedules (dose dense (dd) and metronomic (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; 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.

Zotiraciclib (TG02)

Phase I: In the maximum tolerated dose (MTD) finding part, Temozolomide (TMZ) with two alternate schedules (dose dense (dd) and metronomic (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; 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.

Temozolomide (TMZ)

Jing Wu, M.D.

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 maximum tolerated dose (MTD) of Zotiraciclib (TG02) for Arm 1 (dose dense TMZ) and Arm 2 (metronomic TMZ) independently. Then a randomized cohort expansion compared progression free survival at 4 months (PFS4) of the two arms for an efficient determination of a TMZ schedule to combine with Zotiraciclib at MTD.

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

Participants will be screened with:

* Medical history
* Physical exam
* Blood and urine tests
* Magnetic resonance imaging (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 cyclin-dependent kinases (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 United States (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 cyclin-dependent kinase 9 (CDK9) activity and its target proteins, such as anti-apoptotic protein myeloid-cell leukemia (Mcl-1), X-linked inhibitor of apoptosis (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.

To select the treatment regimen with better progression free survival (PFS)4 between Zotiraciclib (TG02) plus dd TMZ or mn TMZ at each of the MTDs following cohort expansion.

Phase II:

-To determine the efficacy of Zotiraciclib (TG02) plus TMZ versus TMZ alone in patients with recurrent World Health Organization (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 α-thalassemia mental retardation X-linked (ATRX) and/or tumor protein P53 (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).

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

Phase I Trial of 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

We plan to share the Study Protocol, SAP and the Informed Consent Form on ClinicalTrials.gov.

Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

DLT is defined as any adverse events attributed to the study drug. For example, Grade 4 neutropenia lasting 5 days or more. Febrile neutropenia defined as grade 3-4 neutropenia with fever ≥38.5ºC and/or infection requiring antibiotic or antifungal treatment. Nausea or vomiting that responds to symptomatic therapy and lasts ≤7 days. Fatigue that responds to symptomatic therapy and lasts ≤7 days. And weight gain (in patients on steroids).

Maximum tolerated dose of Zotiraciclib (TG02) in combination with dose dense Temozolomide (TMZ) was assessed using the Bayesian Optimal Interval (BOIN) design. The MTD is defined as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate of 0.35. If there are ties, we select the higher dose level when the isotonic estimate is lower than the target toxicity rate; and we select the lower dose level when the isotonic estimate is greater than the target toxicity rate of 0.35.

Maximum tolerated dose of metronomic (mn) Zotiraciclib (TG02) was assessed using the Bayesian Optimal Interval (BOIN) design. The MTD is defined as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate of 0.35. If there are ties, we select the higher dose level when the isotonic estimate is lower than the target toxicity rate; and we select the lower dose level when the isotonic estimate is greater than the target toxicity rate of 0.35.

We first determined the maximum tolerated dose (MTDs) in each ARM and we then performed the cohort expansion at the MTD in both ARMs separately, until we treated a total of 18 participants at this dose in each ARM. PFS is defined as the duration of time from start of registration to time of progression or death, whichever comes first. Progression was assessed by the Response Assessment in Neuro-Oncology Criteria (RANO). Progression is ≥25% increase in tumor volume compared to baseline in the sum of the products of perpendicular diameters of enhancing lesions compared with the smallest measurement obtained either at baseline or best response with the participant on stable or increasing doses of steroids. Significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesions with the participant on stable or increasing doses of steroids (not caused by comorbid events). Any new lesions.

We first determined the MTDs in each ARM and we then performed the cohort expansion at the MTD in both ARMs separately, until we treated a total of 18 participants at this dose in each ARM. PFS is defined as the duration of time from start of registration to time of progression or death, whichever comes first. Progression was assessed by the Response Assessment in Neuro-Oncology Criteria (RANO). Progression is ≥25% increase in tumor volume compared to baseline in the sum of the products of perpendicular diameters of enhancing lesions compared with the smallest measurement obtained either at baseline or best response with the participant on stable or increasing doses of steroids. Significant increase in T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) non-enhancing lesions with the participant on stable or increasing doses of steroids (not caused by comorbid events). Any new lesions.

Median amount of time subject survives without disease progression after treatment

National Cancer Institute (NCI)

Principal Investigator

Temozolomide (TMZ) 125mg/m\^2/day, 7 days on and 7 days off; and Zotiraciclib (TG02) 200mg/day on day 1,12,15, 26 per 28-day cycle and one extra dose given 3 days prior to Day 1 cycle 1.

ARM 1 Dose Level 0 (Starting Dose)

Temozolomide (TMZ) 125mg/m\^2/day, 7 days on and 7 days off; and Zotiraciclib (TG02) 250mg/day on day 1,12,15, 26 per 28-day cycle and one extra dose given 3 days prior to Day 1 cycle 1.

ARM 1 Dose Level 1 (Dose Escalation)

Temozolomide (TMZ) 50mg/m\^2 Daily; and Zotiraciclib (TG02) 200mg/day on day 1,12,15, 26 per 28-day cycle and one extra dose given 3 days prior to Day 1 cycle 1.

ARM 2 Dose Level 0 (Starting Dose)

Temozolomide (TMZ) 50mg/m\^2 Daily; and Zotiraciclib (TG02) 250mg/day on day 1,12,15, 26 per 28-day cycle and one extra dose given 3 days prior to Day 1 cycle 1.

ARM 2 Dose 1 (Dose Escalation)

ARM 2 Dose 0 (Dose De-escalation)

Temozolomide (TMZ) 50mg/m\^2 Daily; and Zotiraciclib (TG02) 300mg/day on day 1,12,15, 26 per 28-day cycle and one extra dose given 3 days prior to Day 1 cycle 1.

ARM 2 Dose Level II (Dose Escalation)

ARM 2 Dose Level I (Dose De-escalation)

ARM 1 Dose Level 1 (MTD Level in ARM1)

Temozolomide (TMZ) 50mg/m\^2 Daily and Zotiraciclib (TG02) 250mg/day on day 1,12,15, 26 per 28-day cycle and one extra dose given 3 days prior to Day 1 cycle 1.

ARM 2 Dose Level 1 (MTD Level in ARM2)

ARM 1 Dose Level 0 - (Starting Dose)

ARM 1 Dose Level 1 - (Dose Escalation)

ARM 2 Dose 1 - (Dose Escalation)

ARM 2 Dose 0 - (Dose De-escalation)

ARM 2 Dose Level II - (Dose Escalation)

ARM 2 Dose Level I - (Dose De-escalation)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Jing Wu

All participants in ARM 1 in MTD finding stage: Phase (Ph) I Arm 1 Dose Level (DL) 0, and Ph I Arm 1 DL1.

All Participants

Phase I: Maximum Tolerated Dose (MTD) of Zotiraciclib in Combination With Dose Dense (dd) Temozolomide (TMZ) in Adult Patients With Recurrent Anaplastic Astrocytoma or Glioblastoma/Gliosarcoma

All participants in ARM2 in MTD finding stage: Phase (Ph) I Arm 2 DL0, Ph I Arm 2 DL1, Ph I Arm 2 Dose 0, Ph I Arm 2 DLII and Ph I DLI.

Phase I: Maximum Tolerated Dose (MTD) of Zotiraciclib (TG02) in Combination of Metronomic (mn) Temozolomide (TMZ) in Adult Patients With Recurrent Anaplastic Astrocytoma or Glioblastoma/Gliosarcoma

13 participants in the ARM1 MTD finding stage and 6 participants in the cohort expansion stage: Phase (Ph) I Arm 1 Dose Level (DL) 1

% of Participants Free of Disease Progression at 4mos Treated w/Zotiraciclib at the Maximum Tolerated Dose in Combination Temozolomide w/Dose Dense Temozolomide Schedules in Adult Patients With Recurrent Anaplastic Astrocytoma or Glioblastoma/Gliosarcoma

13 participants in the ARM 2 MTD finding stage and 7 participants in the cohort expansion stage: Phase (Ph) I Arm 2 DL1.

% of Participants Free of Disease Progression at 4mos Treated w/Zotiraciclib at the Maximum Tolerated Dose (MTD) in Combination With the Metronomic (mn) Temozolomide (TMZ) in Adult Patients With Recurrent Anaplastic Astrocytoma or Glioblastoma/Gliosarcoma

Phase II

This outcome measure was not done because a Phase II study and strategy will be discussed in an upcoming meeting with the FDA to potentially conduct the Phase II as a separate protocol.

Phase II: Progression Free Survival in Subjects Taking Zotiraciclib (TG02) Plus Temozolomide (TMZ) Versus TMZ Alone in Patients With Recurrent World Health Organization (WHO) Grade III or IV Astrocytoma.

Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

Arm2 DI: After prot. amend. previously defined gr 4 lymphopenia was no longer counted as DLT. 2/3 DLTs listed here are no longer DLTs. Arm2 D0:Prot. amend occurred after this dose de-escal. Re-eval. of DLT rate at DL1 led to the next dose escal. Analysis not applic. for Arm1 DL1\& Arm2D. Arm1 DL1:Per study design, pts in expans. stage are not analyzed for DLT. Arm2 DL1:Per study design, pts in expans. stage are not analyzed for DLT;as part of the expans. no pt in this grp were analyzed for DLT.

Spots Global Cancer Trial Database for zotiraciclib (tg02)