ATM-Inhibitor + Radiation for Brain Tumor

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must not be taking: Anticonvulsants, Steroids

Disqualifiers: Pregnancy, Heart failure, Infections, others

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

Compensation: Varies

Number of Visits: 21

67 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking enzyme-inducing anticonvulsants at least two weeks before enrolling. If you are taking more than 8 mg of dexamethasone per day, you will also need to adjust your dosage before joining the trial.

What data supports the effectiveness of the drug WSD0628, an ATM kinase inhibitor, when combined with radiation for treating brain tumors?

Research on similar ATM inhibitors, like AZD1390 and AZ32, shows they can make brain tumors more sensitive to radiation, leading to better tumor control and increased survival in animal models. These inhibitors work by blocking the tumor's ability to repair DNA damage caused by radiation, making the treatment more effective. ^{1 2 3 4 5}

Is the ATM-Inhibitor + Radiation treatment generally safe for humans?

The research does not provide specific safety data for humans, but it shows that ATM inhibitors like AZD1390 and AZ32 have been tested in animal models, where they were effective in enhancing the effects of radiation on tumors. These studies are a step towards understanding their safety and effectiveness in humans. ^{1 2 4 5 6}

How is the drug WSD0628 different from other brain tumor treatments?

WSD0628 is unique because it is an ATM kinase inhibitor that enhances the effectiveness of radiation therapy by making tumor cells more sensitive to radiation. Unlike many treatments, it is designed to penetrate the blood-brain barrier, which is a common challenge in treating brain tumors, allowing it to target brain tumors more effectively. ^{1 2 3 4 7}

What is the purpose of this trial?

The purpose of this study is to test WSD0628 in combination with radiation therapy for recurrent brain tumors.

Research Team

William G. Breen, MD

Principal Investigator

Mayo Clinic

Eligibility Criteria

Adults over 18 with recurrent brain tumors, specifically Glioblastoma or Grade 3/4 astrocytoma, who've had prior radiation and chemo. They must be able to take light-protective measures, provide tissue samples for research, have a life expectancy of at least 3 months, and meet certain health criteria like adequate blood counts and liver function. Pregnant or nursing individuals and those not using contraception are excluded.

Inclusion Criteria

I am willing to protect myself from light during and two weeks after the study.

Minimum life expectancy of at least 3 months

Negative pregnancy test done ≤7 days prior to registration, for persons of childbearing potential only

Exclusion Criteria

I do not have any severe illnesses or social situations that would stop me from following the study's requirements.

I have a long QT interval or risk factors for Torsades de Pointes.

I haven't taken seizure medications or more than 8 mg of steroids daily in the last two weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive WSD0628 treatment starting the day before radiation therapy, which is given for 10 consecutive business days. This phase aims to determine the maximum tolerated dose using the Bayesian Optimal Interval design.

32 months

10 visits (in-person)

Dose Expansion

Participants receive WSD0628 treatment at the recommended Phase 2 dose, starting the day before radiation therapy, which is given for 10 consecutive business days.

12 months

10 visits (in-person)

Tumor Penetrance

One treatment of WSD0628 is given prior to radiation and surgical resection is performed on the same day to evaluate tumor penetrance.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of anti-tumor activity and adverse events.

4 weeks

Treatment Details

Interventions

• WSD0628

Trial Overview The trial is testing WSD0628 combined with radiation therapy on patients with recurrent brain tumors to see if it's effective. Participants will receive the ATM-Inhibitor drug alongside standard radiation treatments.

Participant Groups

Group I: Group C (Tumor Penetrance Treatments) Experimental Treatment 1 Intervention

One treatment of WSD0628 will be given prior to radiation and surgical resection will be performed on the same day. The two doses given will be determined by Group A and Group B. Patients will be randomized in a 1:1 fashion. * Dose level 1: minimally radiosensitizing concentration of WSD0628 will be achieved. * Dose level 2: selected based on a prediction that a maximally radiosensitizing concentration of WSD0628 will be achieved. This portion of the study will open after Group A (Dose Escalation) is complete. This portion of the study will open to patients with recurrent high-grade glioma to further evaluate the efficacy, safety, tolerability, pharmacokinetics and biological activity of WSD0628 when combined with radiation therapy in specific patient subgroups

Group II: Group B (Dose Expansion) Experimental Treatment 1 Intervention

WSD0628 treatment should be started the day before radiation therapy starts (Day 1). Radiation therapy is given for 10 consecutive business days (Day 2-15, not including weekends and holidays), and WSD0628 will only be given on those 10 consecutive business days ≥30 minutes but ≤2 hours before radiation. The Group B (Dose Expansion) portion of the study will be opened after the Group A (Dose Escalation) is complete.

Group III: Group A (Dose Escalation) Experimental Treatment 1 Intervention

WSD0628 treatment should be started the day before radiation therapy starts (Day 1). Radiation therapy is given for 10 consecutive business days (Day 2-15, not including weekends and holidays), and WSD0628 will only be given on those 10 consecutive business days ≥30 minutes but ≤2 hours before radiation.

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

Food and Drug Administration (FDA)

Collaborator

Trials

184

Recruited

1,553,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

AZD1390 is a highly selective ATM inhibitor that effectively penetrates the blood-brain barrier and enhances the effectiveness of radiation therapy in treating brain tumors, as demonstrated in preclinical models.

In combination with radiation, AZD1390 significantly increased tumor regression and survival rates in animal models of glioma and lung-brain metastases, indicating its potential as a promising treatment for central nervous system malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Durant, ST., Zheng, L., Wang, Y., et al.[2021]

The ATM kinase inhibitor KU-60019 significantly enhances the effectiveness of radiation therapy in glioblastoma multiforme (GBM), increasing survival rates in mouse models by 2- to 3-fold compared to controls.

GBM tumors with mutant p53 show greater sensitivity to KU-60019, suggesting that this treatment could be particularly beneficial for patients with this genetic profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Biddlestone-Thorpe, L., Sajjad, M., Rosenberg, E., et al.[2022]

The ATM inhibitor KU-60019 effectively radiosensitizes glioblastoma multiforme (GBM) cells at nanomolar concentrations, enhancing the effectiveness of radiation therapy without interfering with the standard treatment drug temozolomide (TMZ).

KU-60019 not only inhibits the growth of glioma cells but also shows minimal impact on the survival of human embryonic stem cell-derived astrocytes, suggesting a potential for reduced side effects in brain tissue during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. Golding, SE., Rosenberg, E., Adams, BR., et al.[2021]

The study identified two ATM inhibitors, AZ31 and AZ32, with AZ32 showing improved ability to penetrate the blood-brain barrier and effectively radiosensitize glioblastoma multiforme (GBM) cells in vivo, leading to enhanced tumor control.

AZ32 demonstrated a significant increase in apoptosis in tumor cells compared to healthy brain tissue after radiation treatment, suggesting it could improve survival rates in GBM patients while potentially allowing for lower radiation doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice. Karlin, J., Allen, J., Ahmad, SF., et al.[2020]

Two new ATM inhibitors, M3541 and M4076, effectively block DNA repair in cancer cells, enhancing the effectiveness of radiotherapy and leading to complete tumor regressions in mouse models.

These inhibitors showed high potency and selectivity in inhibiting ATM kinase activity, suggesting a promising strategy for improving cancer treatment outcomes when combined with other therapies like PARP and topoisomerase I inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A New Class of Selective ATM Inhibitors as Combination Partners of DNA Double-Strand Break Inducing Cancer Therapies. Zimmermann, A., Zenke, FT., Chiu, LY., et al.[2023]

M6620, an ATR kinase inhibitor, enhances the effectiveness of radiation therapy in treating non-small cell lung cancer (NSCLC) brain metastases, as shown in preclinical models where it improved overall survival compared to radiation alone.

The study found that M6620 disrupts DNA damage repair mechanisms and cell cycle checkpoints, leading to increased cancer cell death when combined with radiation, supporting its potential use in ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATR Inhibitor M6620 (VX-970) Enhances the Effect of Radiation in Non-Small Cell Lung Cancer Brain Metastasis Patient-Derived Xenografts. Baschnagel, AM., Elnaggar, JH., VanBeek, HJ., et al.[2022]

KU-60019, an improved analogue of the ATM inhibitor KU-55933, is significantly more effective at radiosensitizing human glioma cells, being 10-fold more effective at blocking radiation-induced phosphorylation of key ATM targets.

KU-60019 not only enhances the effectiveness of radiation therapy but also inhibits glioma cell migration and invasion, suggesting it could be a dual-action treatment that targets both tumor growth and response to radiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Golding, SE., Rosenberg, E., Valerie, N., et al.[2022]

References

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

The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. [2021]

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

ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. [2022]

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

Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. [2021]

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

Orally Bioavailable and Blood-Brain Barrier-Penetrating ATM Inhibitor (AZ32) Radiosensitizes Intracranial Gliomas in Mice. [2020]

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

A New Class of Selective ATM Inhibitors as Combination Partners of DNA Double-Strand Break Inducing Cancer Therapies. [2023]

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

ATR Inhibitor M6620 (VX-970) Enhances the Effect of Radiation in Non-Small Cell Lung Cancer Brain Metastasis Patient-Derived Xenografts. [2022]

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

Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. [2022]