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TG02 Plus Dose-Dense or Metronomic Temozolomide Followed by Randomized Phase II Trial of TG02 Plus Temozolomide Versus Temozolomide Alone in Adults With Recurrent Anaplastic Astrocytoma and Glioblastoma

NCT02942264

Description:

Background: 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 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 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 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 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 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
  • Glioma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: TG02 Plus Dose-Dense or Metronomic Temozolomide Followed by Randomized Phase II Trial of TG02 Plus Temozolomide Versus Temozolomide Alone in Adults With Recurrent Anaplastic Astrocytoma and Glioblastoma
  • Official Title: Phase I Trial of TG02 Plus Dose-Dense or Metronomic Temozolomide Followed by Randomized Phase II Trial of 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
TG02Phase I Arm 1
TMZPhase I Arm 1

Purpose

Background: 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 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: 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 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 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 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:

        -  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 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 TG02 down-regulates CDK9 activity and its
           target proteins, such as anti-apoptotic protein Mcl-1, XIAP and survivin. A treatment
           with 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 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 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.

        -  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 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 + 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 (TMZ alone) will be offered the
           opportunity to continue TMZ and additional treatment with TG02.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I Arm 1Experimentaldose dense TMZ 125 mg/m2 x 7 days on / 7days off plus TG02 dose escatlation
  • TG02
  • TMZ
Phase I Arm 2Experimentalmetronomic TMZ 50 mg/ m2 daily plus TG02 doseescalation
  • TG02
  • TMZ
Phase II Arm 1ExperimentalMTD of TG02 from phase I plus and "winner" of dd vs metronomic TMZ from phase I
  • 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, p53).

          -  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 greater than or equal to 60

          -  Patients must have adequate bone marrow function (ANC greater than or equal to
             1,500/mm^3, platelet count of greater than or equal to 100,000/mm^3, adequate liver
             function less than or equal to 3 times upper limit normal and alkaline phosphatase
             less than or equal to 2 times upper limit normal, total bilirubin less than or equal
             to 1.5mg/dl), and adequate renal function (BUN less than or equal to 1.5 times
             institutional normal and serum creatinine less than 1.5 mg/dl prior to registration.
             These tests must be performed within 14 days 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, 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 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 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 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 as per section

          -  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 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 TG02.

          -  Patients with a history of any other cancer (except non-melanoma skin cancer 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.

          -  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:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: maximum tolerated dose (MTD) of 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:

Secondary Outcome Measures

Measure:The treatment regimen with better PFS4 between TG02 plus dd TMZ or mn TMZ at each of the MTDs following cohort expansion.
Time Frame:4 weeks after initiation of treatment
Safety Issue:
Description:
Measure:Objective response rate, PFS at 6 months (PFS6) and overall survival(OS) in the treatment arms.
Time Frame:At 6 months, at time of death
Safety Issue:
Description:
Measure:Relationship between symptoms and disease progression and treatment tolerance
Time Frame:End of study therapy (at disease progression or occurence of intolerable toxicity)
Safety Issue:
Description:
Measure:Patient's symptom severity and interference with function rating error bar graphs for each symptom severity
Time Frame:At each measurable timepoint
Safety Issue:
Description:
Measure:Mean core symptom severity, mean severity of the MDASI, and mean symptom interference
Time Frame:At time of clinical evaluation
Safety Issue:
Description:
Measure:Estimates of differences in the mean symptom severity and mean symptom interference between responders and non-responders will be estimated in the intent to treat population
Time Frame:Overall
Safety Issue:
Description:

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

October 4, 2017