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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

Description:

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 MTD of Zotiraciclib (TG02) for Arm 1 (dose dense TMZ) and Arm 2 (metronomic TMZ) independently. In Phase II part, a Bayesian design based on posterior probability will be used to monitor eficacy. Participants will be screened with: - Medical history - Physical exam - Blood and urine tests - 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.

Related Conditions:
  • Anaplastic Astrocytoma
  • Anaplastic Oligoastrocytoma
  • Glioblastoma
  • Gliosarcoma
  • WHO Grade III Glioma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 170009
  • SECONDARY ID: 17-C-0009
  • NCT ID: NCT02942264

Conditions

  • Brain Tumor
  • Astrocytoma
  • Astroglioma
  • Glioblastoma
  • Gliosarcoma

Interventions

DrugSynonymsArms
Zotiraciclib (TG02)Phase I Arm 1
TMZPhase I Arm 1

Purpose

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 MTD of Zotiraciclib (TG02) for Arm 1 (dose dense TMZ) and Arm 2 (metronomic TMZ) independently. In Phase II part, a Bayesian design based on posterior probability will be used to monitor eficacy. Participants will be screened with: - Medical history - Physical exam - Blood and urine tests - 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 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 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 CDK9
           activity and its target proteins, such as anti-apoptotic protein Mcl-1, 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.

      Phase II:

      -To determine the efficacy of Zotiraciclib (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 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).
    

Trial Arms

NameTypeDescriptionInterventions
Phase I Arm 1Experimentaldose dense TMZ 125 mg/m2 x 7 days on / 7days off plus Zotiraciclib (TG02) dose escatlation
  • Zotiraciclib (TG02)
  • TMZ
Phase I Arm 2Experimentalmetronomic TMZ 50 mg/ m2 daily plus Zotiraciclib (TG02) doseescalation
  • Zotiraciclib (TG02)
  • TMZ
Phase II Arm 1ExperimentalMTD of Zotiraciclib (TG02) from phase I plus and "winner" of dd vs metronomic TMZ from phase I
  • Zotiraciclib (TG02)
  • TMZ
Phase II Arm 2Active Comparator"winner" of dd vs metronomic TMZ from phase I alone
  • TMZ

Eligibility Criteria

        -  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 Zotiraciclib (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 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.

        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 Zotiraciclib (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 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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: 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.
Time Frame:4 weeks after initiation of treatment
Safety Issue:
Description:maximum tolerated dose of Zotiraciclib (TG02)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Brain Tumor
  • Glioblastoma
  • Relapse
  • Randomized
  • Temodar

Last Updated

January 10, 2020