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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

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ClinicalTrials.gov Identifier: NCT02942264
Recruitment Status : Recruiting
First Posted : October 24, 2016
Last Update Posted : July 6, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Brain Tumor Astrocytoma Astroglioma Glioblastoma Gliosarcoma Drug: TG02 Drug: TMZ Phase 1 Phase 2

  Hide Detailed Description

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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 152 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : October 21, 2016
Estimated Primary Completion Date : August 2, 2021
Estimated Study Completion Date : August 2, 2022


Arm Intervention/treatment
Experimental: Phase I Arm 1
dose dense TMZ 125 mg/m2 x 7 days on / 7days off plus TG02 dose escatlation
Drug: 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 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 + 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 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 + TG02 versus dd/mn TMZ alone using a Bayesian clinical trial design.

Experimental: Phase I Arm 2
metronomic TMZ 50 mg/ m2 daily plus TG02 doseescalation
Drug: 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 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 + 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 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 + TG02 versus dd/mn TMZ alone using a Bayesian clinical trial design.

Experimental: Phase II Arm 1
MTD of TG02 from phase I plus and "winner" of dd vs metronomic TMZ from phase I
Drug: 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 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 + 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 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 + TG02 versus dd/mn TMZ alone using a Bayesian clinical trial design.

Active Comparator: Phase II Arm 2
"winner" of dd vs metronomic TMZ from phase I alone
Drug: TMZ
Phase I: 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; 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.




Primary Outcome Measures :
  1. 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 ]
  2. Phase II: progression free survival in subjects taking TG02 plus TMZ versus TMZ alone in patients with recurrent WHO grade III or IV astrocytoma. [ Time Frame: Disease progression ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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 ]
  3. Relationship between symptoms and disease progression and treatment tolerance [ Time Frame: End of study therapy (at disease progression or occurence of intolerable toxicity) ]
  4. Patient's symptom severity and interference with function rating error bar graphs for each symptom severity [ Time Frame: At each measurable timepoint ]
  5. Mean core symptom severity, mean severity of the MDASI, and mean symptom interference [ Time Frame: At time of clinical evaluation ]
  6. 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02942264


Contacts
Contact: Christine M Bryla, R.N. (240) 760-6007 brylacm@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Jing Wu, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02942264     History of Changes
Other Study ID Numbers: 170009
17-C-0009
First Posted: October 24, 2016    Key Record Dates
Last Update Posted: July 6, 2018
Last Verified: September 27, 2017

Studies a U.S. FDA-regulated Drug Product: Yes

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Brain Tumor
Glioblastoma
Relapse
Randomized
temodar

Additional relevant MeSH terms:
Glioblastoma
Brain Neoplasms
Astrocytoma
Gliosarcoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents