ATM-Inhibitor + Radiation for Brain Tumor

Recruiting at 1 trial location

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

94 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for individuals with recurrent brain tumors, focusing on a drug called WSD0628 (an ATM kinase inhibitor) combined with radiation therapy. The goal is to determine the safety and effectiveness of this combination for treating brain tumors that have returned after previous treatment. The trial includes different groups to test varying doses and strategies to identify the best approach. Individuals with a history of high-grade glioma, whose condition worsened after prior treatments, might be suitable candidates for this study. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

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

Research has shown that WSD0628, a new treatment under testing, is designed to be safe for humans. Some studies have found that it can effectively reach the brain, which is crucial for treating brain tumors. This capability allows it to target the tumor while minimizing harm to other brain areas.

WSD0628 enhances the effects of radiation therapy, a common treatment for brain tumors, by blocking a specific DNA repair process in tumor cells, making them more sensitive to radiation. Studies describe the compound as non-toxic, meaning it doesn’t cause harm when used as intended.

As a Phase 1 trial, this study is in the early stages of human testing. Phase 1 trials primarily focus on safety and determining the correct dosage. While there is limited human safety data so far, the trial's progression to this phase suggests that initial safety findings are promising. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about WSD0628 because it offers a unique approach to treating brain tumors. Unlike standard treatments that primarily focus on radiation alone, WSD0628 is an ATM inhibitor, which may enhance the effectiveness of radiation therapy by making cancer cells more sensitive to radiation damage. Additionally, this treatment is designed to be administered just before radiation, potentially maximizing its impact. This novel combination might lead to more effective tumor control and opens up new possibilities in treating aggressive brain tumors.

What evidence suggests that this trial's treatments could be effective for recurrent brain tumors?

Studies have shown that WSD0628, a new treatment under investigation in this trial, can effectively reach brain tumors. This is important because it may enhance the effects of radiation therapy. In tests with brain cancer models, WSD0628 helped shrink tumors more effectively when combined with radiation. Research indicates that WSD0628 is designed to cross the blood-brain barrier, a major challenge for many treatments. This combined approach appears safe and promising for treating aggressive brain tumors like glioblastomas. Participants in this trial will receive WSD0628 in different treatment arms, including dose escalation, dose expansion, and tumor penetrance treatments, to evaluate its efficacy and safety when combined with radiation therapy. ^{1 3 4 5 6}

Who Is on the Research Team?

William G. Breen, MD

Principal Investigator

Mayo Clinic

Jann N. Sarkaria, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

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

Measurable disease as defined in Section 11.0

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40230030/

The novel brain penetrant ATM inhibitor WSD0628 ... The small molecule ATM kinase inhibitor WSD0628 was specifically designed for enhanced distribution across the blood brain barrier to more effectively treat ...

2. mayo.edu mayo.edu/research/documents/the-radiosensitizing-effects-of-the-novel-brain-penetrant-and-potent-atm-inhibitor-wsd0628-in-glioblastoma-and-melanoma-patient-derived-xenografts/doc-20556017

The radiosensitizing effects of the novel brain penetrant ... In patient-derived intracranial xenograft models of. Glioblastoma and Melanoma, WSD-0628 produced significant efficacy in combination with radiation therapy. • ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-06935

ATM-Inhibitor WSD0628 in Combination with Radiation ... WSD0628 is able to get into tumors in the brain, so this treatment may be safe and effective in treating patients with high-grade gliomas when given along with ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05917145?term=AREA%5BConditionSearch%5D(Glioblastoma)%20AND%20SEARCH%5BLocation%5D(AREA%5BLocationCountry%5DUnited%20States%20AND%20AREA%5BLocationState%5DMinnesota)%20AND%20AREA%5BOverallStatus%5D(RECRUITING%20OR%20ENROLLING_BY_INVITATION)&rank=6

Study Details | NCT05917145 | ATM-Inhibitor WSD0628 in ... The purpose of this study is to test WSD0628 in combination with radiation therapy for recurrent brain tumors. Detailed Description. High grade gliomas are the ...

5. jpet.aspetjournals.org jpet.aspetjournals.org/article/S0022-3565(24)00204-0/abstract

Preclinical Systemic Pharmacokinetics, Dose ... This study evaluates the preclinical systemic pharmacokinetics, dose proportionality, and mechanisms influencing CNS distribution of WSD0628, a novel ATM ...

6. medchemexpress.com medchemexpress.com/wsd0628.html?srsltid=AfmBOoqou8t80ZEwFZ2KvRQrWCH_Gq86DEmz12A51iX4Osuxxqd7Q1mH

WSD0628 | ATM Inhibitor WSD0628 is a brain penetrant and potent ATM inhibitor with profound radiosensitizing effect. For research use only. We do not sell to patients. WSD0628 Chemical ...