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Escalation/de-escalation dose levels of zotiraciclib given in 28 day cycles

Estimated RP2D of zotiraciclib given in 28 day cycles

One RP2D dose of zotiraciclib given on the day prior to brain tumor biopsy or resection, a continuation of treatment with estimated RP2D of zotiraciclib given in 28 days cycles following the recovery of the surgery

Zotiraciclib will be given orally at the DL1, DL-1, or DL 2 once a day on days 1, 4, 8, 11, 15, 18 of every 28-days cycle (18 cycles total).

Zotiraciclib

NCI NOB Referral Group

Jing Wu, M.D.

National Cancer Institute Referral Office

Background:

Diffuse gliomas are tumors that affect the brain and spinal cord. Gliomas that develop in people with certain gene mutations (IDH1 or IDH2) are especially aggressive. Better treatments are needed.

Objective:

To see if a study drug (zotiraciclib) is effective in people with recurrent diffuse gliomas who have IDH1 or IDH2 mutations.

Eligibility:

People aged 18 years and older with diffuse gliomas that returned after treatment. They must also have mutations in the IDH1 or IDH2 genes.

Design:

Participants will be screened. They will have a physical exam with blood and urine tests. They will have tests of their heart function. They will have an MRI of their brain. A new biopsy may be needed if previous results are not available.

Zotiraciclib is a capsule taken by mouth with a glass of water. Participants will take the drug at home on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. They may also be given medications to prevent side effects of the study drug. The schedule for taking the study drug may vary for participants who will undergo surgery.

Participants will be given a medication diary for each cycle. They will write down the date and time of each dose of the study drug.

Participants will visit the clinic about once a month. They will have a physical exam, blood tests, and tests to evaluate their heart function. An MRI of the brain will be repeated every 8 weeks.

Participants may remain in the study for up to 18 cycles (1.5 years).

...

Background:

* Zotiraciclib is a multi-kinase inhibitor that has been shown to have anti-glioma effects through transcriptional suppression, mitochondrial dysfunction, and adenosine 5'-triphosphate (ATP) reduction in glioblastoma in our preclinical studies
* Zotiraciclib is orally administered and likely penetrates the blood brain barrier (BBB). There has been a clinical experience in using zotiraciclib as a single agent and in combination with other chemotherapy agents in cancers, including malignant gliomas
* Our phase I study of zotiraciclib and temozolomide (TMZ) in recurrent high-grade astrocytomas determined the maximum tolerated dose (MTD) of zotiraciclib in combination with TMZ and demonstrated the safety of the treatment in recurrent high-grade glioma patients
* Preliminary efficacy analysis of Phase I demonstrated an improved response to zotiraciclib in combination with TMZ in IDH-mutant gliomas compared to the IDH-wildtype counterpart
* A selective vulnerability to zotiraciclib as a single agent was demonstrated in the preclinical models of IDH-mutant gliomas

Objectives:

* Phase I: To estimate recommended phase II dose (RP2D) of zotiraciclib
* Phase II: To determine 12-months progression free survival (PFS) in participants with recurrent glioma, IDH1/2-mutant, World Health Organization (WHO) grade 3 treated with zotiraciclib in comparison with the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors

Eligibility:

* Age \>=18; Karnofsky performance status (KPS) \>=70%
* Histological confirmation of diffuse glioma, WHO grades 2-4 with IDH1/2 mutation status confirmed by DNA sequence
* Have recurrent disease
* Have prior treatment of radiation and/or conventional chemotherapies
* No prior use of bevacizumab as a treatment for a brain tumor

Design:

* This is a phase I/II study to evaluate the safety and efficacy of zotiraciclib as a single agent in recurrent IDH-mutant gliomas.
* Initially, 9-24 participants (Cohort 1) will be assigned to Phase I to estimate recommended phase 2 dose (RP2D) of zotiraciclib.
* Once RP2D is estimated, we will start enrollment into cohorts for Phase II, non-surgical participants (Cohorts 2-4), and surgical (Cohort 5). Considering non-evaluable participants and screen failures, this trial plans to enroll 96 participants total.
* Drug will be administered on days 1, 4, 8, 11, 15, 18 in cycles of 28 days for a maximum of 18 cycles. Starting dose is 200 mg. In the case that 200 mg is not tolerable, a lower dose 150mg, will be evaluated. If 200 mg is tolerated well, a higher dose level will be evaluated at 250mg.
* Participants in the surgical cohort will get an additional single pre-treatment with one dose of study drug at the RP2D on Day 1 of Cycle 0, followed by brain tumor biopsy or surgical resection within 24 hours on Day 2 of Cycle 0. Approximately 2-4 weeks after surgery or biopsy participants in this Cohort will continue treatment with the study drug and start Day 1 of Cycle 1.

Study of Zotiraciclib for Recurrent High-Grade Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations

A Phase I/II Study of Zotiraciclib for Recurrent High-Grade Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Proportion of patients that have progressive disease after 12 months

Amount of time until disease progression from initiation of study therapy as compared with data of the brain tumor database

Type, grade and frequency of adverse events

Amount of time subject survives after initiation of study therapy as compared with data of the brain tumor database

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Zotiraciclib for Recurrent High-Grade Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations	NCT05588141	Brain Tumor Cancer	Zotiraciclib	18 Years -	National Institutes of Health Clinical Center (CC)
Study of Zotiraciclib for Recurrent High-Grade Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations	NCT05588141	Brain Tumor Cancer	Zotiraciclib	18 Years -	National Institutes of Health Clinical Center (CC)

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