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
- Conditions
- GlioblastomaAstrogliomaGliosarcomaBrain TumorAstrocytoma
- Interventions
- Registration Number
- NCT02942264
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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.
- Detailed Description
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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 53
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase I Arm 1 Dose Dense Temozolomide plus Zotiraciclib (TG02) Zotiraciclib (TG02) dose dense (dd) Temozolomide (TMZ) 125 mg/m\^2 x 7 days on / 7 days off plus Zotiraciclib (TG02) dose escalation Phase I Arm 2 Metronomic Temozolomide Plus Zotiraciclib (TG02) Zotiraciclib (TG02) metronomic Temozolomide (TMZ) 50 mg/ m\^2 daily plus Zotiraciclib (TG02) dose escalation Phase II Arm 1 Maximum Tolerated Dose (MTD) of Zotiraciclib (TG02) Plus Temozolomide (TMZ) Zotiraciclib (TG02) Maximum tolerated dose (MTD) of Zotiraciclib (TG02) from phase I plus and "winner" of dose dense (dd) vs metronomic Temozolomide (TMZ) from phase I Phase I Arm 2 Metronomic Temozolomide Plus Zotiraciclib (TG02) Temozolomide (TMZ) metronomic Temozolomide (TMZ) 50 mg/ m\^2 daily plus Zotiraciclib (TG02) dose escalation Phase I Arm 1 Dose Dense Temozolomide plus Zotiraciclib (TG02) Temozolomide (TMZ) dose dense (dd) Temozolomide (TMZ) 125 mg/m\^2 x 7 days on / 7 days off plus Zotiraciclib (TG02) dose escalation Phase II Arm 1 Maximum Tolerated Dose (MTD) of Zotiraciclib (TG02) Plus Temozolomide (TMZ) Temozolomide (TMZ) Maximum tolerated dose (MTD) of Zotiraciclib (TG02) from phase I plus and "winner" of dose dense (dd) vs metronomic Temozolomide (TMZ) from phase I Phase II Arm 2 Metronomic Temozolomide (TMZ) Temozolomide (TMZ) "winner" of dose dense (dd) vs metronomic Temozolomide (TMZ) from phase I alone
- Primary Outcome Measures
Name Time Method 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 4 weeks after initiation of treatment 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.
% 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 4 months 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.
% 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 4 months 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.
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. Disease progression Median amount of time subject survives without disease progression after treatment
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 4 weeks after initiation of treatment 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.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
National Institutes of Health Clinical Center🇺🇸Bethesda, Maryland, United States