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

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 >=15; Karnofsky performance status (KPS) >=70%
• Histological confirmation of diffuse glioma, WHO grades 2-4 with IDH1/2 mutation status confirmed by DNA sequencing
• 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). This trial plans to enroll up 64 evaluable participants.
• 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 150 mg, will be evaluated. If 200 mg is tolerated well, a higher dose level will be evaluated at 250 mg.
• 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.

• 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