Recruiting

Phase 1

Phase 2

ZotiraciclibA Phase I/II Study of Zotiraciclib for Recurrent Malignant Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations

Sponsor:

National Cancer Institute (NCI)

Code:

NCT05588141

Conditions

Brain Tumor

Cancer

Eligibility Criteria

Sex: All

Age: 15+

Healthy Volunteers: Not accepted

Interventions

Zotiraciclib

Study Details

Brief summary:

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 15 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).

Conditions

Brain Tumor

Cancer

Study ID

NCT05588141

Start date

May 16, 2023

Status verified date

Aug 12, 2026

Completion date

Aug 2, 2032

Anticipated

Primary completion date

Aug 1, 2028

Anticipated

Eligibility Criteria

Sex: All

Age: 15+

Healthy Volunteers: Not accepted

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 TruSight(TM) Oncology 500 performed in LP, NCI or prior documentation of IDH1 or IDH2 mutation status
Participants must have received prior treatment (e.g., radiation, conventional chemotherapy, or vorasidenib) 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 >15 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 (per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0)
Individuals of child-bearing potential (IOCBP) and men must agree to use highly effective contraception (hormonal, intrauterine device (IUD), abstinence, tube ligation, partner has had a 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, parent or legal guardian of minor 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 disease relapse in those with initial diagnosis of WHO grade 3-4, or more than two disease relapses in those with initial diagnosis of WHO grade 2 for Phase II. For Phase I enrollment, there are no limits on the number of prior recurrences.
Prior therapy with:

any investigational agent (including IDH mutant inhibitor) 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 correction formula on screening electrocardiogram (ECG) (QTCf can be used; QTCb can be used for participants with sinus bradycardia)
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 beta-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

Study Design

Enrollment

96 participants

Anticipated

Allocation

Non randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: 1

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

experimental: 2

Estimated RP2D of zotiraciclib given in 28 day cycles

experimental: 3

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

Interventions

Zotiraciclib

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).

Primary outcome measure

To determine 12 months PFS in participants w/ recurrent glioma, IDH1/2-mutant, WHO grade 3 treated w/ zotiraciclib in comparison w/ the established brain tumor database matched for tumor molecular characteristics and clinical prognostic factors [ Time Frame: 12 Months ]
To estimate recommended phase II dose (RP2D) of zotiraciclib [ Time Frame: 28 days ]

Central Contacts and Locations

Central contacts

NCI NOB Referral Group

(866) 251-9686 ncinobreferrals@mail.nih.gov

Jing Wu, M.D.

(240) 760-6036 jing.wu3@nih.gov

Locations

National Institutes of Health Clinical Center

Recruiting

Bethesda, Maryland, United States, 20892

Contacts

National Cancer Institute Referral Office

888-624-1937

More Information

Sponsor

National Cancer Institute (NCI)

Last update posted

Aug 28, 2026

Last verified

Aug 12, 2026

Keywords

Brain Tumor
Glioma
Idh Mutation
Recurrent Disease

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by National Cancer Institute (NCI) on 2026-08-28.