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

Study Overview
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Brief Summary
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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). ...

Detailed Description
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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.

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

Conditions
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Brain Tumor, Cancer

Intervention / Treatment
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* Drug: Zotiraciclib


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Participants must have diffuse glioma, WHO grades 2-4, histologically confirmed by Laboratory of Pathology, NCI IDH1 or IDH2 mutation status confirmed by TSO500 performed in LP, NCI Participants must have received prior treatment (e.g., radiation, conventional chemotherapy) prior to disease progression Participants must have recurrent disease, proven histologically or by imaging studies Participants who have undergone prior surgical resection are eligible for enrollment to cohorts 1-4. Age >=18 years Karnofsky >=70% Participants must have adequate organ and marrow function as defined below: leukocytes >3,000/microliter absolute neutrophil count (ANC) >1,500/microliter platelets >100,000/microliter total bilirubin <=2x ULN (ULN 1.3 mg/dl) except for participants with Gilbert Syndrome AST < 3x ULN (ULN 34U/L) ALT < 3x ULN (ULN 55U/L) serum creatinine < 1.5 mg/dL calculated creatinine clearance by CKD-EPI equation > 60 cc/min Participants must have recovered from the adverse effects of prior therapy to grade 2 or less Women of child-bearing potential (WOCBP) and men must agree to use highly effective contraception (hormonal, intrauterine device (IUD), abstinence, tube ligation, partner has had the previous vasectomy) at the study entry, for the duration of study treatment, and up to 3 months after the last dose of zotiraciclib Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 3 months after study treatment discontinuation Participants must be scheduled for brain tumor biopsy or surgical resection at NIH (Cohort 5 only) The ability of a participant to understand and the willingness to sign a written informed consent document. No Legally Authorized Representative can provide initial consent. EXCLUSION CRITERIA: More than one prior disease relapse (WHO grade 3-4) or more than two prior disease relapses (WHO grade 2) Prior therapy with: any investigational agent and/or standard of care cytotoxic therapy within 28 days prior to treatment initiation vincristine within 14 days prior to treatment initiation nitrosoureas within 42 days prior to treatment initiation procarbazine within 21 days prior to treatment initiation non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, within 7 days prior to treatment initiation surgery within 14 days prior to treatment initiation radiation therapy within 30 days prior to treatment initiation bevacizumab for tumor treatment. Note: participants who received bevacizumab for symptom management, including but not limited to cerebral edema, or pseudo progression can be enrolled Prolonged QTc >470ms as calculated by Fridericia s correction formula on screening electrocardiogram (ECG) Prior invasive malignancies within the past 3 years prior to study treatment initiation (with the exception of non-melanoma skin cancers, carcinoma in situ of the cervix, melanoma in situ, or any localized cancer for whom the systemic standard of care therapy is not required) History of allergic reactions attributed to compounds of similar chemical composition to zotiraciclib, such as flavopiridol Pregnancy (confirmed with <=-HCG serum or urine pregnancy test performed at screening) Uncontrolled intercurrent illness or social situations that would limit compliance with study requirements Uncontrolled primary diabetes mellitus

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Escalation/de-escalation dose levels of zotiraciclib given in 28 day cycles | Drug: Zotiraciclib<br>* 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).<br>|
| Experimental: 2<br>Estimated RP2D of zotiraciclib given in 28 day cycles | Drug: Zotiraciclib<br>* 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).<br>|
| Experimental: 3<br>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 | Drug: Zotiraciclib<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine 12-months progression free survival (PFS) in participants with recurrent glioma, IDH1/2-mutant, WHO grade 3 treated with zotiraciclib in comparison with the established brain tumor database matched for tumor molecular characteristic... | Proportion of patients that have progressive disease after 12 months | 12 Months | 
| To estimate recommended phase II dose (RP2D) of zotiraciclib | Number of DLTs within the DLT Period | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the efficacy of treatment with zotiraciclib in participants with recurrent glioma, IDH1/2-mutant WHO grade 3 in comparison with the established brain tumor database by 3 years PFS rate | Amount of time until disease progression from initiation of study therapy as compared with data of the brain tumor database | 3 years | 
| To determine the safety of zotiraciclib in participants with recurrent glioma, IDH1/2-mutant WHO grades 2-4 | Type, grade and frequency of adverse events | Day 1 of Cycle 0 (Cohort 5) or Day 1 of Cycle 1 (Cohorts 1-4) through 30 days after the study agent was last administered will be collected on the days study drug is administered, and at the safety follow up visit. | 
| To determine the efficacy of treatment with zotiraciclib in participants with recurrent glioma, IDH1/2-mutant WHO grade 3 in comparison with the established brain tumor database by 5 years overall survival (OS) rate | Amount of time subject survives after initiation of study therapy as compared with data of the brain tumor database | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Tumor, Glioma, Idh Mutation, Recurrent Disease