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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of a new drug, zotiraciclib, for treating aggressive brain tumors called diffuse gliomas. These tumors have returned after previous treatments and are linked to specific gene mutations, IDH1 or IDH2, which make them difficult to treat. Participants will take the drug over a 28-day cycle, with regular check-ups and MRIs to monitor progress. The trial seeks participants aged 15 and older who have these gene mutations and have experienced a return of their glioma after prior treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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.

Is there any evidence suggesting that zotiraciclib is likely to be safe for humans?

Research has shown that zotiraciclib has been tested for safety in people with brain tumors. In earlier studies, researchers combined it with another drug, TMZ, to assess its safety and compare it to using TMZ alone. Zotiraciclib blocks certain signals in cancer cells, potentially stopping their growth.

The available data suggest that the treatment is generally well-tolerated. However, like many cancer treatments, it can cause side effects such as nausea, tiredness, or changes in blood counts. Participants in these studies often received additional medications to manage side effects.

For those considering joining a trial, discussing potential risks and benefits with a healthcare team is crucial. They can provide insights into how previous participants responded to zotiraciclib. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for brain cancer?

Unlike the standard treatments for brain cancer, which often include surgery, radiation, and chemotherapy, Zotiraciclib offers a novel approach. Researchers are excited about Zotiraciclib because it targets specific cell cycle proteins that are crucial for cancer cell growth, potentially leading to more effective tumor control. This mechanism of action is different from most existing therapies and could provide a new avenue for treatment, especially for patients who have not responded well to traditional options. Additionally, Zotiraciclib is being explored in various dosing strategies, including pre-surgical administration, which might enhance its effectiveness and improve surgical outcomes.

What evidence suggests that zotiraciclib might be an effective treatment for brain cancer?

Research has shown that zotiraciclib is a promising treatment for brain tumors, including recurrent tumors with specific genetic changes called IDH1 or IDH2 mutations. Zotiraciclib blocks certain proteins, known as cyclin-dependent kinases (CDKs), which aid cancer cell growth and survival. This drug can penetrate the brain, making it a strong option for brain cancer treatment. Early studies found that zotiraciclib affects several pathways that promote the growth of glioblastoma, a type of brain cancer, potentially slowing tumor growth. Although more research is needed, these early results suggest that zotiraciclib may effectively treat aggressive brain tumors. Participants in this trial will receive zotiraciclib in various dosing regimens, including escalation/de-escalation dose levels, estimated RP2D, and a specific dosing schedule before brain tumor biopsy or resection. ^{2 5 6 7 8}

Who Is on the Research Team?

Jing Wu, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38159337/

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the ... Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02942264

NCT02942264 | Zotiraciclib (TG02) Plus Dose-Dense or ... Study Overview. Background: Zotiraciclib (TG02) is an investigational drug that penetrates the blood-brain barrier and might treat brain tumors.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8197750/

Phase I Study of Zotiraciclib in Combination with ... These preclinical findings suggest that zotiraciclib targets multiple survival pathways in glioblastoma and synergistically decreases cellular energy production ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05588141

A Phase I/II Study of Zotiraciclib for Recurrent Malignant ... To see if a study drug (zotiraciclib) is effective in people with recurrent diffuse gliomas who have IDH1 or IDH2 mutations.

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2018-03365

Zotiraciclib (TG02) Plus Dose-Dense or Metronomic ... Objective: To find out if Zotiraciclib (TG02) is safe, and to find out if it in combination with TMZ is as effective as TMZ alone in people with brain tumors.

6. clinicalstudies.info.nih.gov clinicalstudies.info.nih.gov/ProtocolDetails.aspx?id=17-C-0009

Phase I Trial of Zotiraciclib (TG02) Plus Dose-Dense or ... To find out if Zotiraciclib (TG02) is safe, and to find out if it in combination with TMZ is as effective as TMZ alone in people with brain tumors. Eligibility:.

7. synapse.patsnap.com synapse.patsnap.com/drug/e9357b3ff7e14d619bddf1e0d8efc73c

Zotiraciclib - Drug Targets, Indications, Patents A Phase I/II Study of Zotiraciclib for Recurrent Malignant Gliomas With Isocitrate Dehydrogenase 1 or 2 (IDH1 or IDH2) Mutations

8. go.drugbank.com go.drugbank.com/drugs/DB16656

Zotiraciclib: Uses, Interactions, Mechanism of Action The multi-kinase inhibitor TG02 induces apoptosis and blocks B-cell receptor signaling in chronic lymphocytic leukemia through dual mechanisms of action.