Overview

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

Status:
Completed
Trial end date:
2020-08-26
Target enrollment:
0
Participant gender:
All
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.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
National Cancer Institute (NCI)
Treatments:
Temozolomide
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 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,

- 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 magnetic
resonance imaging (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. 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 positron emission
tomography (PET) scan) in which case the principal investigators discretion may
determine appropriate timepoint at which study therapy may begin.

- Women of childbearing potential must have a negative beta-human chorionic gonadotropin
(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 Neuro-oncology Branch (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 Temozolomide (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 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.