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

NCT02942264 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 17000917-C-0009
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

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.

Conditions

Glioblastoma; Gliosarcoma; Brain Tumor; Astrocytoma; Astroglioma

Keywords

Brain Tumor; Glioblastoma; Relapse; Randomized; Temodar

Outcome Measures

Primary Outcomes (5)

• 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

  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.

  4 weeks after initiation of treatment

• 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

  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.

  4 weeks after initiation of treatment

• % 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

  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.

  4 months

• % 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

  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.

  4 months

• 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.

  Median amount of time subject survives without disease progression after treatment

  Disease progression

Other Outcomes (2)

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

  Date treatment consent signed to date off study, approximately 15mo(m)/8days(d), 26m, 7m/26d, 13m/17d, 11m/30d, 12m/6d, 19m/11d, 9m/28d and 18m/21d for Group 1-9 respectively.

• Phase I: Number of Participants With a Dose-limiting Toxicity (DLT)

  4 weeks after initiation of treatment

Study Arms (4)

Phase I Arm 1 Dose Dense Temozolomide plus Zotiraciclib (TG02)

EXPERIMENTAL

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

Drug: Zotiraciclib (TG02); Drug: Temozolomide (TMZ)

Phase I Arm 2 Metronomic Temozolomide Plus Zotiraciclib (TG02)

EXPERIMENTAL

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

Drug: Zotiraciclib (TG02); Drug: Temozolomide (TMZ)

Phase II Arm 1 Maximum Tolerated Dose (MTD) of Zotiraciclib (TG02) Plus Temozolomide (TMZ)

EXPERIMENTAL

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

Drug: Zotiraciclib (TG02); Drug: Temozolomide (TMZ)

Phase II Arm 2 Metronomic Temozolomide (TMZ)

ACTIVE COMPARATOR

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

Drug: Temozolomide (TMZ)

Interventions

Zotiraciclib (TG02) DRUG

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.

Also known as: TG02

Phase I Arm 1 Dose Dense Temozolomide plus Zotiraciclib (TG02); Phase I Arm 2 Metronomic Temozolomide Plus Zotiraciclib (TG02); Phase II Arm 1 Maximum Tolerated Dose (MTD) of Zotiraciclib (TG02) Plus Temozolomide (TMZ)

Temozolomide (TMZ) DRUG

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.

Also known as: Temodar

Phase I Arm 1 Dose Dense Temozolomide plus Zotiraciclib (TG02); Phase I Arm 2 Metronomic Temozolomide Plus Zotiraciclib (TG02); Phase II Arm 1 Maximum Tolerated Dose (MTD) of Zotiraciclib (TG02) Plus Temozolomide (TMZ); Phase II Arm 2 Metronomic Temozolomide (TMZ)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have pathologic diagnosis of anaplastic astrocytoma defined as World Health Organization (WHO) grade III or glioblastoma/gliosarcoma, WHO grade IV, which are confirmed by National Cancer Institute (NCI) Laboratory of Pathology. If the pathology diagnosis is anaplastic glioma or anaplastic oligoastrocytoma, evidence of either intact combined loss of the short arm chromosome 1 (i.e. 1p) and the long arm of chromosome 19 (1p/19q) chromosomes or molecular features suggesting astrocytic tumor must be present (including, but not limited to alpha-thalassemia/mental retardation, alpha-thalassemia/mental retardation, X-linked (ATRX), tumor protein P53 (TP53).
• Patients must have recurrent disease, histologically proven or imaging suggestive of recurrent disease as determined by principal investigator (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 procarbazine, lomustine (CCNU) and vincristine (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 (absolute neutrophil count (ANC) \> 1,500/mm\^3, platelet count of \> 100,000/mm\^3), adequate liver function (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)\< 3 times upper limit normal and alkaline phosphatase \< 2 times upper limit normal, total bilirubin \< 1.5mg/dl), and adequate renal function (blood urea nitrogen (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 Common Terminology Criteria (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,

You may not qualify if:

• Patients who are receiving any other investigational agents. However, prior enrollment on a study using investigational agents is acceptable
• 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 human immunodeficiency virus (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 Cytochrome P450 1A2 (CYP1A2) and Cytochrome P450 3A4 (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 corrected QT interval (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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. doi: 10.1056/NEJMoa043330.

  PMID: 15758009 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Brain Neoplasms; Astrocytoma; Glioblastoma; Gliosarcoma; Recurrence

Interventions

14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene; Temozolomide

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Jing Wu
• Organization: National Cancer Institute

jing.wu3@nih.gov

240-760-6036

Study Officials

• Jing Wu, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 21, 2016
• First Posted: October 24, 2016
• Study Start: December 14, 2016
• Primary Completion: August 26, 2020
• Study Completion: August 26, 2020
• Last Updated: February 23, 2026
• Results First Posted: September 28, 2021

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Study Protocol, SAP, and Informed Consent Form will be available indefinitely after summary results data is published on clinicaltrials.gov.
• Access Criteria: Study Protocol, SAP, and Informed Consent Form will be accessible via clinicaltrials.gov.

Locations

US (1)