Zotiraciclib for Brain Cancer

Overseen By NCI NOB Referral Group

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents, Vincristine

Disqualifiers: Prolonged QTc, Prior invasive malignancies, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 11

Duration: 18 months

96 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, certain treatments like investigational agents, vincristine, nitrosoureas, procarbazine, and some non-cytotoxic agents must not have been used within specific time frames before starting the trial.

What makes the drug Zotiraciclib unique for treating brain cancer?

Zotiraciclib is unique because it is designed to penetrate the blood-brain barrier (a protective layer that prevents many drugs from reaching the brain), which is a significant challenge in treating brain cancers. This ability to reach the brain effectively sets it apart from many other treatments that struggle to do so. ^{1 2 3 4 5}

What is the purpose of this trial?

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).

Research Team

Jing Wu, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults with recurrent high-grade gliomas and IDH1 or IDH2 mutations can join this trial. They must have had prior treatment, be willing to use contraception, and not be breastfeeding. Participants need good organ function and cannot have had multiple relapses or other recent cancers.

Inclusion Criteria

I can understand and am willing to sign the consent form myself.

I am mostly able to care for myself but may not be able to do active work.

Women of child-bearing potential (WOCBP) and men must agree to use highly effective contraception at the study entry, for the duration of study treatment, and up to 3 months after the last dose of zotiraciclib

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical composition to zotiraciclib

I have not taken certain medications recently.

Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive zotiraciclib orally on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle, with a maximum of 18 cycles

18 months

Monthly visits (in-person) for physical exams, blood tests, and heart function tests; MRI every 8 weeks

Surgical Pre-treatment

Participants in the surgical cohort receive a single pre-treatment dose of zotiraciclib followed by brain tumor biopsy or surgical resection

1 day

1 visit (in-person) for surgery

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person) for safety follow-up

Treatment Details

Interventions

• Zotiraciclib

Trial Overview The study is testing Zotiraciclib's effectiveness for aggressive brain tumors with specific gene mutations. Patients take the drug orally in cycles, alongside regular clinic visits for exams, heart tests, MRIs, and maintaining a medication diary.

Participant Groups

Group I: 3 Experimental Treatment 1 Intervention

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

Group II: 2 Experimental Treatment 1 Intervention

Estimated RP2D of zotiraciclib given in 28 day cycles

Group III: 1 Experimental Treatment 1 Intervention

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

Zotiraciclib is already approved in United States, European Union for the following indications:

Approved in United States as Zotiraciclib for:

• Orphan designation for gliomas

Approved in European Union as Zotiraciclib for:

• Orphan designation for gliomas

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

AZD1775 demonstrated effective penetration across the blood-brain barrier in glioblastoma patients, with a tumor-to-plasma concentration ratio indicating significant drug accumulation in tumors.

The study revealed that the acidic environment of tumors enhances AZD1775 uptake via specific transporters, while factors like blood-brain barrier integrity and transporter activity contribute to variability in drug penetration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients Using an IVIVE-PBPK Modeling Approach. Li, J., Wu, J., Bao, X., et al.[2019]

Tucatinib, approved by the FDA for advanced HER2-positive breast cancer, significantly improved progression-free survival (PFS) and overall survival (OS) compared to placebo, particularly benefiting patients with brain metastases, who comprised 48% of the study population.

The HER2CLIMB trial demonstrated a favorable benefit-risk profile for tucatinib, although it is associated with safety concerns such as diarrhea and hepatotoxicity, which are important to monitor during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer. Shah, M., Wedam, S., Cheng, J., et al.[2022]

In a study of 42 female patients with HER2-positive breast cancer and brain metastasis, pyrotinib demonstrated a high disease control rate of 92.8% and an objective response rate of 47.6% for central nervous system lesions, indicating its efficacy in managing this challenging condition.

The treatment was associated with manageable toxicity, with 36% of patients experiencing adverse reactions, and it resulted in a median progression-free survival of 16.6 months for brain metastases, suggesting that pyrotinib is a promising option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of pyrotinib in treating HER2-positive breast cancer patients with brain metastasis: A multicenter study. Gao, M., Fu, C., Li, S., et al.[2022]

Osimertinib shows promising ability to penetrate the blood-brain barrier (BBB), which is crucial for treating brain malignancies that are difficult to manage due to limited therapeutic access to the central nervous system.

The discussion highlights two innovative kinase inhibitors, AZD3759 and AZD1390, as examples of successful drug discovery aimed at enhancing BBB penetration, potentially leading to better treatment options for CNS malignancies and disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building on the success of osimertinib: achieving CNS exposure in oncology drug discovery. Colclough, N., Chen, K., Johnström, P., et al.[2022]

In a study of 239 patients with HER2-positive metastatic breast cancer, pyrotinib-based therapy showed promising long-term outcomes, with median overall survival (OS) of 29.07 months for second-line treatment and 22.23 months for third-or-higher-line treatment.

For patients with brain metastasis (BM), median progression-free survival (PFS) was 7.50 months and median OS was 21.27 months, indicating that pyrotinib is effective even in this challenging subgroup, especially when combined with brain radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Outcome Analysis of Pyrotinib in Patients With HER2-Positive Metastatic Breast Cancer and Brain Metastasis: A Real-World Study. Liang, X., Gui, X., Yan, Y., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients Using an IVIVE-PBPK Modeling Approach. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Tucatinib for the Treatment of Patients with Advanced or Metastatic HER2-positive Breast Cancer. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

The efficacy and safety of pyrotinib in treating HER2-positive breast cancer patients with brain metastasis: A multicenter study. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Building on the success of osimertinib: achieving CNS exposure in oncology drug discovery. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Long-term Outcome Analysis of Pyrotinib in Patients With HER2-Positive Metastatic Breast Cancer and Brain Metastasis: A Real-World Study. [2023]