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

NCT05588141 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10000860000860-C
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 1

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

Cancer; Brain Tumor

Keywords

Brain Tumor; Glioma; Idh Mutation; Recurrent Disease

Outcome Measures

Primary Outcomes (2)

• 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

  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 Outcomes (3)

• 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

  3 years

• To determine the safety of zotiraciclib in participants with recurrent glioma, IDH1/2-mutant WHO grades 2-4

  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

  5 years

Study Arms (3)

1

EXPERIMENTAL

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

Drug: Zotiraciclib

2

EXPERIMENTAL

Estimated RP2D of zotiraciclib given in 28 day cycles

Drug: Zotiraciclib

3

EXPERIMENTAL

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

Interventions

Zotiraciclib DRUG

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).

1; 2; 3

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (5)

• Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res. 2016 Sep 1;22(17):4291-301. doi: 10.1158/1078-0432.CCR-16-0592. Epub 2016 Jul 12.

  PMID: 27407096 BACKGROUND

• Miller JJ, Loebel F, Juratli TA, Tummala SS, Williams EA, Batchelor TT, Arrillaga-Romany I, Cahill DP. Accelerated progression of IDH mutant glioma after first recurrence. Neuro Oncol. 2019 May 6;21(5):669-677. doi: 10.1093/neuonc/noz016.

  PMID: 30668823 BACKGROUND

• Wu J, Yuan Y, Long Priel DA, Fink D, Peer CJ, Sissung TM, Su YT, Pang Y, Yu G, Butler MK, Mendoza TR, Vera E, Ahmad S, Bryla C, Lindsley M, Grajkowska E, Mentges K, Boris L, Antony R, Garren N, Siegel C, Lollo N, Cordova C, Aboud O, Theeler BJ, Burton EM, Penas-Prado M, Leeper H, Gonzales J, Armstrong TS, Calvo KR, Figg WD, Kuhns DB, Gallin JI, Gilbert MR. Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas. Clin Cancer Res. 2021 Jun 15;27(12):3298-3306. doi: 10.1158/1078-0432.CCR-20-4730. Epub 2021 Mar 30.

  PMID: 33785481 BACKGROUND

• Pang Y, Li Q, Sergi Z, Yu G, Kim O, Lu P, Chan M, Sang X, Wang H, Ranjan A, Robey RW, Soheilian F, Tran B, Nunez FJ, Zhang M, Song H, Zhang W, Davis D, Gilbert MR, Gottesman MM, Liu Z, Thomas CJ, Castro MG, Gujral TS, Wu J. Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib. iScience. 2025 Mar 25;28(4):112283. doi: 10.1016/j.isci.2025.112283. eCollection 2025 Apr 18.

  PMID: 40241769 DERIVED

• Pang Y, Li Q, Sergi Z, Yu G, Sang X, Kim O, Wang H, Ranjan A, Merchant M, Oudit B, Robey RW, Soheilian F, Tran B, Nunez FJ, Zhang M, Song H, Zhang W, Davis D, Gilbert MR, Gottesman MM, Liu Z, Khan J, Thomas CJ, Castro MG, Gujral TS, Wu J. Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib. bioRxiv [Preprint]. 2024 Jan 2:2023.06.29.547143. doi: 10.1101/2023.06.29.547143.

  PMID: 37786680 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Brain Neoplasms; Neoplasms; Glioma; Recurrence

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Jing Wu, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

NCI NOB Referral Group

CONTACT

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

Jing Wu, M.D.

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 15, 2022
• First Posted: October 20, 2022
• Study Start: May 16, 2023
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 2, 2032
• Last Updated: June 11, 2026

Record last verified: 2026-03-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (1)