AZD1390 for Glioblastoma

Overseen By Phase 0 Navigator

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Nader Sanai

Must be taking: Levetiracetam

Must not be taking: Coumarin anticoagulants, CYP3A4 inducers

Disqualifiers: Pregnancy, Severe infection, Cardiac conditions, others

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

Compensation: Varies

Number of Visits: 4

97 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called AZD1390 for individuals with glioblastoma, a serious brain tumor. Researchers aim to determine the effectiveness of AZD1390 when combined with standard radiation therapy. Participants may have either a newly diagnosed or recurring Grade 4 glioma and must require radiation as part of their treatment plan. Those with measurable brain lesions who have undergone surgery or standard therapies may find this trial suitable. As a Phase 1 trial, the research focuses on understanding how AZD1390 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention that you cannot use certain medications like coumarin-derived anticoagulants and strong inhibitors or inducers of CYP3A4. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AZD1390, when combined with radiation therapy, is generally safe for patients with glioblastoma, a type of brain cancer. In one study involving 115 patients, about 16% experienced significant side effects from AZD1390. These side effects were serious but not life-threatening, and no patients encountered the most severe side effects.

The study found that a dose of 400 mg was tolerable for some patients, while others managed well with 300 mg. This indicates that while some side effects can occur, they are usually manageable with careful monitoring. ^{1 2 3 4 5}

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

Researchers are excited about AZD1390 because it targets glioblastoma in a unique way. Unlike standard treatments like surgery, radiation, and chemotherapy, AZD1390 is designed to inhibit DNA-dependent protein kinase (DNA-PK), a crucial enzyme involved in repairing DNA damage in cancer cells. This mechanism potentially enhances the effectiveness of radiation therapy by preventing cancer cells from repairing themselves, thereby making them more vulnerable. By targeting this specific pathway, AZD1390 offers a novel approach that could improve outcomes for patients with this aggressive brain cancer.

What evidence suggests that AZD1390 might be an effective treatment for glioblastoma?

Research has shown that AZD1390 may help treat glioblastoma, a very aggressive brain cancer. This trial includes different arms to study AZD1390 in various contexts. Studies have found that using AZD1390 with radiation can increase cancer cells' sensitivity to the treatment. Early results are promising, especially for patients with recurring Grade 4 glioma. AZD1390 also has a manageable safety profile, meaning patients tolerated the side effects. This combination treatment could potentially lead to better outcomes for people with glioblastoma. ^{1 4 5 6 7}

Who Is on the Research Team?

Nader Sanai, MD

Principal Investigator

Chief Scientific Officer/Director

Are You a Good Fit for This Trial?

This trial is for adults over 18 with newly diagnosed or recurrent WHO Grade 4 glioma (a type of brain tumor) who are planning to have radiation. They must have measurable disease, stable seizures if present, and good organ function. Pregnant women, those with certain heart conditions or severe infections, and individuals on specific medications are excluded.

Inclusion Criteria

My blood tests show my organs and bone marrow are working well.

I can take pills by mouth.

For females of reproductive potential: use of highly effective contraception and agreement to use such a method during study participation

Exclusion Criteria

I have risk factors for abnormal heart rhythms.

Known allergic reactions to components of the AZD1390

I have a history of fainting due to heart issues, irregular heartbeats, or sudden cardiac arrest.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 0

Participants undergo pharmacokinetic analysis of AZD1390 in tumor tissue

Intraoperative

1 visit (in-person)

Phase 1b Expansion

Participants receive therapeutic dosing of AZD1390 plus standard-of-care fractionated radiotherapy

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• AZD1390

Trial Overview The study tests AZD1390 in combination with standard radiotherapy. It includes a Phase 0 part where patients' PK response is assessed and a Phase 1b expansion for responders. The goal is to see how well AZD1390 works alongside usual cancer treatments.

How Is the Trial Designed?

Group I: Arm C: Newly-diagnosed Grade 4 Glioma Experimental Treatment 1 Intervention

Group II: Arm B: Recurrent Grade 4 Glioma Dose Escalation Experimental Treatment 1 Intervention

Group III: Arm A: Recurrent Grade 4 Glioma Surgical Cohort Time Escalation Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Nader Sanai

Lead Sponsor

Trials

11

Recruited

440+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Ivy Brain Tumor Center

Collaborator

Trials

12

Recruited

910+

Barrow Neurological Institute

Collaborator

Trials

27

Recruited

7,100+

Published Research Related to This Trial

Temozolomide (TMZ) and the checkpoint kinase inhibitor AZD7762 both showed time- and concentration-dependent cytotoxic effects on human glioma cells, with their combination resulting in synergistic effects that enhance cell death.

The combination treatment of TMZ and AZD7762 not only suppressed the expression of the DNA repair protein MGMT but also modulated several signaling pathways, suggesting a complex mechanism that may improve the efficacy of glioma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and AZD7762 Induce Synergistic Cytotoxicity Effects on Human Glioma Cells. Chen, Y., Tseng, BJ., Tsai, YH., 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. redjournal.org redjournal.org/article/S0360-3016(24)00979-9/fulltext

Safety and Preliminary Efficacy of AZD1390 + Radiation ... Preliminary efficacy is encouraging in Arm A. These data suggest the potential for AZD1390 to act as a radiosensitizer for the treatment of GBM.

2. aacr.org aacr.org/about-the-aacr/newsroom/news-releases/azd1390-with-radiotherapy-shows-manageable-safety-profile-and-preliminary-efficacy-for-patients-with-glioblastoma-in-phase-i-trial/

AZD1390 With Radiotherapy Shows Manageable Safety ... AZD1390, an ataxia telangiectasia mutant (ATM) kinase inhibitor, demonstrated a manageable safety profile in both recurrent and newly diagnosed glioblastoma ( ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05182905

AZD1390 in Recurrent and Newly Diagnosed WHO Grade ... This is an open-label, single-center Phase 0/1b study that will enroll at least 27 participants with recurrent WHO Grade 4 Glioma requiring re-radiation.

4. gcaresearch.org gcaresearch.org/news/global-coalition-for-adaptive-research-announces-evaluation-of-azd1390-in-gbm-agile-trial/

GCAR Announces Evaluation of AZD1390 in GBM AGILE ... ... AZD1390 with radiotherapy showed a manageable safety profile and preliminary efficacy for patients with glioblastoma in a Phase I trial.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0360301624009799

Safety and Preliminary Efficacy of AZD1390 + Radiation ... Preliminary efficacy is encouraging in Arm A. These data suggest the potential for AZD1390 to act as a radiosensitizer for the treatment of GBM.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03423628

A Study to Assess the Safety and Tolerability of AZD1390 ... This Phase 1 study will assess safety and tolerability of AZD1390 in combination with radiation therapy (RT) in brain malignancies. The combination cohorts have ...

7. ivybraintumorcenter.org ivybraintumorcenter.org/brain-tumor-clinical-trials/current-trials/azd1390-for-recurrent-glioblastoma/

azd1390 for grade 4 glioma - Clinical Trials A Phase 0/1b clinical trial to evaluate AZD1390 in patients with recurrent and newly diagnosed WHO grade 4 glioma.