Testing zotiraciclib for recurrent brain tumors with specific gene mutations

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

This study is testing a new drug called zotiraciclib to see if it can help people aged 15 and older with recurring brain tumors that have certain gene mutations.

Quick facts

• Phase: PHASE1; PHASE2
• Study type: Interventional
• Enrollment: 96 (estimated)
• Ages: 15 Years and up
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (nih)
• Drugs / interventions: bevacizumab, chemotherapy, radiation
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT05588141 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate the effectiveness of zotiraciclib, a multi-kinase inhibitor, in patients with recurrent diffuse gliomas that have IDH1 or IDH2 mutations. Participants aged 15 and older will undergo screening, including physical exams, blood tests, and MRIs, to confirm eligibility. The drug will be administered orally at home on specific days of a 28-day cycle, with additional medications provided to manage potential side effects. The study will assess the recommended dose and measure progression-free survival over 12 months compared to established databases.

Who should consider this trial

Good fit: Ideal candidates include individuals aged 15 and older with recurrent diffuse gliomas and confirmed IDH1 or IDH2 mutations.

Not a fit: Patients with gliomas that do not have IDH1 or IDH2 mutations may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with aggressive brain tumors that currently have limited treatment options.

How similar studies have performed: Preliminary analyses from earlier studies have shown promise for zotiraciclib in treating IDH-mutant gliomas, indicating potential for success in this approach.

Eligibility criteria

* 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

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (RECRUITING)

Study contacts

• Principal investigator: Jing Wu, M.D. — National Cancer Institute (NCI)
• Study coordinator: NCI NOB Referral Group

Conditions: Brain Tumor, Cancer, Glioma, Idh Mutation, Recurrent Disease