Accepts Healthy Volunteers
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.
An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.
Searching Both is inclusive of interventional and observational studies.
|Eligible Ages||18 Years and Over|
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.
- - Patients must have recurrent disease, histologically proven or imaging suggestive of recurrent disease as determined by PI.
- - 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.
- - 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.
- - 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.
- - 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.
- - 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.
- - Patients who are receiving any other investigational agents.
- - Patients with prior bevacizumab use for tumor treatment.
- - 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.
- - 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, 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.
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.
Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
|Phase 1/Phase 2|
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.
|National Cancer Institute (NCI)|
The person who is responsible for the scientific and technical direction of the entire clinical study.
|Jing Wu, M.D.|
|Principal Investigator Affiliation||National Cancer Institute (NCI)|
Category of organization(s) involved as sponsor (and collaborator) supporting the trial.
The disease, disorder, syndrome, illness, or injury that is being studied.
|Brain Tumor, Astrocytoma, Astroglioma, Glioblastoma, Gliosarcoma|
|Study Website:||View Trial Website|
- - 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).
- - Temozolomide (TMZ) is an oral alkylating agent that has proven efficacy in anaplastic glioma and glioblastoma.
- - 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.
- - Documented pathology diagnosis of anaplastic astrocytoma [WHO grade III], or glioblastoma/gliosarcoma (WHO grade IV) with recurrent disease.
- - 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.
- - Phase I: - This portion of the study is conducted in two stages: The MTD finding and cohort extension.
- - 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.#46;mn) TMZ + Zotiraciclib (TG02) versus dd/mn TMZ alone using a Bayesian clinical trial design.
- - 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).
Experimental: Phase I Arm 1
dose dense TMZ 125 mg/m2 x 7 days on / 7days off plus Zotiraciclib (TG02) dose escatlation
Experimental: Phase I Arm 2
metronomic TMZ 50 mg/ m2 daily plus Zotiraciclib (TG02) doseescalation
Experimental: Phase II Arm 1
MTD of Zotiraciclib (TG02) from phase I plus and "winner" of dd vs metronomic TMZ from phase I
Active Comparator: Phase II Arm 2
"winner" of dd vs metronomic TMZ from phase I alone
Drug: - Zotiraciclib (TG02)
Phase I: 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; 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.
Drug: - TMZ
Phase I: 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; 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.
Contact a Trial Team
If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892