AZD1390 + Radiation Therapy for Brain Cancer

Recruiting at 8 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must be taking: Anti-epileptic prophylaxis

Must not be taking: CYP3A4 inhibitors, Seizurogenic medications

Disqualifiers: Seizure history, Severe COPD, others

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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2-6 weeks

180 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will test an investigational drug called AZD1390 in combination with radiation therapy for the treatment of brain tumors. This is the first time AZD1390 is being given to patients. This study will test safety, tolerability and PK (how the drug is absorbed, distributed and eliminated) of ascending doses of AZD1390 in combination with distinct regimens of radiation therapy

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) before starting the study drug. Specifically, you must stop immune checkpoint inhibitors 28 days before and other agents 7 days before starting the trial. Hormonal therapies are allowed during the study for patients in Arm B.

What data supports the effectiveness of the treatment AZD1390 + Radiation Therapy for Brain Cancer?

Research shows that advanced radiation techniques like intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) are effective in precisely targeting cancer cells while sparing healthy tissue, which can reduce side effects and improve outcomes in various cancers, including brain metastases. ^{1 2 3 4 5}

Is AZD1390 + Radiation Therapy safe for humans?

The safety of advanced radiation therapy techniques like intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) has been studied, showing some risks of gastrointestinal and genitourinary toxicities, but these techniques are generally considered safe with careful use. However, specific safety data for AZD1390 combined with radiation therapy is not provided in the available research. ^{6 7 8 9 10}

What makes the AZD1390 + Radiation Therapy treatment for brain cancer unique?

AZD1390 combined with radiation therapy is unique because it potentially enhances the effectiveness of radiation by targeting specific pathways in cancer cells, which may improve treatment outcomes compared to traditional radiation therapy alone. ^{11 12 13 14 15}

Research Team

Deborah Forst, MD

Principal Investigator

Massachusetts General Hospital

Jan Drappatz, MD

Principal Investigator

UPMC Hospital Radiation Oncology

Patrick Wen, MD

Principal Investigator

Dana-Farber Cancer Institute

Brandon Imber, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Mariza Daras

Principal Investigator

VCU Massey Cancer Center

Anthony Chalmers

Principal Investigator

Beatson West of Scotland Cancer Centre

Rajesh Jena

Principal Investigator

Cambridge University Hospitals NHS Foundation Trust

Susan Short

Principal Investigator

University of Leeds

Eligibility Criteria

This trial is for adults with brain cancer who have completed first-line radiation at least 6 months ago, are willing to take anti-epileptic drugs if needed, and have their disease under control. They must not have had recent chemotherapy or certain other treatments and should be able to undergo MRI scans. People with severe medical conditions, a history of significant brain injury or stroke, uncontrolled seizures, or those on strong CYP3A4 inhibitors/inducers are excluded.

Inclusion Criteria

My cancer outside the brain is under control for treatment in Arm B.

I haven't had lung radiation in the last 8 weeks.

I finished my first round of radiation 6 months ago for Arm A.

Exclusion Criteria

Patient not eligible for sequential MRI evaluations are not eligible for this study

I don't have serious side effects from previous treatments, except for hair loss.

I have not had a heart attack or severe heart issues in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AZD1390 in combination with radiation therapy. Arm A: 35 Gy over 2 weeks, Arm B: 30 Gy over 2 weeks, Arm C: 60 Gy over 6 weeks.

2-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of event-free survival and objective response rate.

1 year

Open-label extension (optional)

Participants may opt into continuation of treatment long-term to assess overall survival and other long-term outcomes.

15 months

Treatment Details

Interventions

• AZD1390
• Radiation Therapy

Trial Overview The study tests AZD1390 in combination with radiation therapy on patients with brain tumors. It's the first time this drug is being used on humans and will assess its safety and how it's processed by the body when given in different doses alongside various radiation schedules.

Participant Groups

Group I: AZD1390 + Radiation Therapy Experimental Treatment 2 Interventions

AZD1390 + Radiation Therapy

Radiation Therapy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in United States as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Canada as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Japan as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in China as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Approved in Switzerland as Radiation Therapy for:

• Cancer treatment
• Palliative care
• Oropharyngeal cancer
• Breast cancer
• Prostate cancer
• Lung cancer
• Brain tumors

Who Is Running the Clinical Trial?

AstraZeneca

Lead 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

Findings from Research

In a study of 379 patients with non-metastatic Stage III-IV head and neck squamous cell cancer, IMRT with simultaneous integrated boost (IMRT+SIB) showed similar effectiveness in local control and survival rates compared to traditional 3D conformal radiotherapy (3D-CRT) and sequential IMRT (IMRTseq).

IMRT+SIB significantly reduced acute toxicity, with lower rates of severe mucositis, dermatitis, and the need for feeding tubes during treatment, suggesting it is a safer option for patients undergoing chemoradiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of 3D confromal radiotherapy and intensity modulated radiotherapy with or without simultaneous integrated boost during concurrent chemoradiation for locally advanced head and neck cancers. Spiotto, MT., Weichselbaum, RR.[2021]

In a study of 22 patients with locally advanced rectal cancer, image-guided radiotherapy (IGRT) led to complete surgical resection in all cases, with 32% of patients showing no residual tumor after treatment.

The treatment was associated with minimal toxicity, although one patient experienced severe side effects likely due to an overdose of capecitabine, suggesting that IGRT is a promising approach for reducing complications in rectal cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of image-guided radiotherapy for locally advanced rectal cancer. Nguyen, NP., Ceizyk, M., Almeida, F., et al.[2011]

Radiation therapy for brain metastases in 58 patients showed no radiogenic complications and improved neurological status in 72% of cases, indicating it is a safe and effective treatment option.

The mean survival time after radiation therapy was 213 days, with better outcomes for patients with breast cancer (347 days) compared to those with lung cancer (152 days), highlighting the importance of tumor type and other factors like age and overall health in prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Results of radiotherapy in brain metastasis]. Schultze, J., Kaya, A., Kimmig, B.[2006]

In a study of 836 prostate cancer patients, those who received image-guided radiotherapy (IGRT) had a 5-year overall survival rate of 88%, which was not significantly different from the 86% survival rate of patients who did not receive IGRT, indicating that IGRT does not negatively impact survival outcomes.

The study found no significant differences in mortality rates from prostate cancer, other cancers, or cardiovascular issues between the IGRT and non-IGRT groups, suggesting that IGRT is a safe option for localized prostate cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of image-guided radiotherapy in definitive radiotherapy for localized prostate cancer: a population-based analysis. Kuo, YH., Liang, JA., Chen, GH., et al.[2022]

Proton therapy (PT) significantly reduces exposure to normal tissues, particularly pelvic bone marrow and small bowel, compared to 3D conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) in patients with resectable rectal cancer, which may lower the risk of acute hematologic toxicity.

All treatment plans were effective in targeting the tumor, but the reduced normal tissue exposure with PT could allow for safer and more aggressive chemotherapy options during and after neoadjuvant chemoradiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protons offer reduced bone marrow, small bowel, and urinary bladder exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer. Colaco, RJ., Nichols, RC., Huh, S., et al.[2022]

Image-guided radiation therapy (IGRT) has evolved significantly and is now widely used in routine clinical practice, emphasizing the importance of quality and patient safety in its application across various treatment techniques and anatomical sites.

The American Society for Radiation Oncology recommends a comprehensive quality-assurance program and an interdisciplinary team approach to ensure IGRT is performed safely and effectively, highlighting the need for ongoing updates to practice guidelines as technology advances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality and Safety Considerations in Image Guided Radiation Therapy: An ASTRO Safety White Paper Update. Qi, XS., Albuquerque, K., Bailey, S., et al.[2023]

In a study involving 18 patients with early-stage central lung tumors, online adaptive intensity modulated proton therapy (IMPT) significantly reduced the mean dose to the bronchial tree compared to MR-guided radiotherapy (MRgRT), suggesting a safer treatment option with lower toxicity risks.

Both non-adaptive and online adaptive IMPT showed significant reductions in the mean doses to the ipsilateral lung and heart compared to MRgRT, indicating improved dose sparing for organs-at-risk during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of MR-guided radiotherapy accumulated doses for central lung tumors with non-adaptive and online adaptive proton therapy. Rabe, M., Palacios, MA., van Sörnsen de Koste, JR., et al.[2023]

In a study of 421 patients undergoing salvage radiotherapy (SRT) after prostate surgery, the use of advanced techniques like intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT) significantly reduced the incidence of late gastrointestinal (GI) toxicities to 4.8%.

However, increasing the radiation dose to 68 Gy or more was linked to a higher risk of genitourinary (GU) toxicities, indicating that while advanced techniques can help minimize some side effects, higher doses may still pose risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy. Tomita, N., Uchiyama, K., Mizuno, T., et al.[2021]

Intensity-modulated radiation therapy (IMRT) resulted in significantly lower rates of acute and late genitourinary (GU) and gastrointestinal (GI) toxicity compared to (125)I seed implants, with 3-year rates of 3.5% GU and 2.4% GI toxicity for IMRT versus 19.2% GU and 7.7% GI for (125)I.

Both treatments showed similar biochemical failure rates, with IMRT having a 4-year freedom from failure rate of 99.5% compared to 93.5% for (125)I, indicating that while both are effective, IMRT may be safer with fewer side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of acute and chronic toxicity for men with low-risk prostate cancer treated with intensity-modulated radiation therapy or (125)I permanent implant. Eade, TN., Horwitz, EM., Ruth, K., et al.[2022]

In a study of 192 patients with localized prostate cancer, using prostate-based IGRT (P-IGRT) resulted in significantly lower acute gastrointestinal toxicities compared to bony structure-based IGRT (B-IGRT), with rates of 3% versus 11%.

Both P-IGRT and B-IGRT showed similar prostate-specific antigen failure-free survival rates at 3 years (95.5% for P-IGRT and 92.7% for B-IGRT), indicating that P-IGRT can reduce toxicity without compromising tumor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decreased acute toxicities of intensity-modulated radiation therapy for localized prostate cancer with prostate-based versus bone-based image guidance. Nakamura, K., Mizowaki, T., Inokuchi, H., et al.[2018]

A new method for delivering interstitial radiation therapy using 192Ir seeds in brain tumors has been developed, which involves CT-guided stereotactic localization and computerized dose planning.

Preliminary results from seven patients show promising outcomes with no serious complications reported, indicating the method's potential safety and efficacy in treating brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of brain tumors with iridium-192 seeds. Kaneko, I., Noguchi, M., Kogure, T., et al.[2019]

In a study of 59 patients with brain metastases from non-small-cell lung cancer and melanoma, the timing between immunotherapy and stereotactic radiotherapy (SRT) did not significantly affect the local control of tumors or the incidence of severe toxicities.

The main predictor of toxicity was tumor volume, with only 5.1% of patients experiencing grade 3 or higher toxicities, indicating that SRT combined with immunotherapy is generally safe regardless of the timing of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases. Cabanie, C., Biau, J., Durando, X., et al.[2021]

Whole-brain radiotherapy (WBRT) combined with temozolomide (TMZ) significantly improves the objective response rate in patients with brain metastases from non-small-cell lung cancer (NSCLC), with a relative risk of 1.43 based on a meta-analysis of 25 clinical trials.

However, this combination treatment also increases the risk of severe hematological (grade III-IV) and gastrointestinal toxicities compared to WBRT alone, indicating a need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response and safety of whole-brain radiotherapy plus temozolomide for patients with brain metastases of non-small-cell lung cancer: A meta-analysis. Han, J., Qiu, M., Su, L., et al.[2022]

In a study of 128 patients with brain metastases from non-small cell lung cancer, synchronous stereotactic radiotherapy (SRT) combined with temozolomide (TMZ) and whole brain radiotherapy (WBRT) significantly improved overall survival (OS) and progression-free survival (PFS) compared to SRT with WBRT alone, with median OS of 13.1 months and PFS of 11.2 months in the TMZ group.

While the combination treatment led to a higher incidence of nausea and vomiting (67.2% vs. 43.8%), other adverse reactions were similar between the two groups, indicating that the treatment is generally tolerable despite some side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of synchronous stereotactic radiotherapy with temozolomide combined with whole brain radiotherapy in treating brain metastases originating from non-small cell lung cancer. Liu, P., Ren, R., You, D., et al.[2021]

In a study of 179 patients with non-small cell lung cancer, renal cell carcinoma, or melanoma treated with immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS), the combination showed a low local failure rate of 5.8%, suggesting effective intracranial control when these treatments are used together.

Higher PD-L1 expression (≥50%) was linked to increased rates of grade 2+ radiation necrosis (17% vs. 3%), indicating that while the combination therapy is generally safe, patients with high PD-L1 levels may need closer monitoring for potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy. Hall, J., Lui, K., Tan, X., et al.[2023]

References

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

Comparison of 3D confromal radiotherapy and intensity modulated radiotherapy with or without simultaneous integrated boost during concurrent chemoradiation for locally advanced head and neck cancers. [2021]

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

Effectiveness of image-guided radiotherapy for locally advanced rectal cancer. [2011]

3. Germany pubmed.ncbi.nlm.nih.gov

[Results of radiotherapy in brain metastasis]. [2006]

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

Safety of image-guided radiotherapy in definitive radiotherapy for localized prostate cancer: a population-based analysis. [2022]

5. China pubmed.ncbi.nlm.nih.gov

Protons offer reduced bone marrow, small bowel, and urinary bladder exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer. [2022]

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

Quality and Safety Considerations in Image Guided Radiation Therapy: An ASTRO Safety White Paper Update. [2023]

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

Comparison of MR-guided radiotherapy accumulated doses for central lung tumors with non-adaptive and online adaptive proton therapy. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Impact of advanced radiotherapy techniques and dose intensification on toxicity of salvage radiotherapy after radical prostatectomy. [2021]

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

A comparison of acute and chronic toxicity for men with low-risk prostate cancer treated with intensity-modulated radiation therapy or (125)I permanent implant. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

Decreased acute toxicities of intensity-modulated radiation therapy for localized prostate cancer with prostate-based versus bone-based image guidance. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Treatment of brain tumors with iridium-192 seeds. [2019]

12. France pubmed.ncbi.nlm.nih.gov

Toxicity and time lapse between immunotherapy and stereotactic radiotherapy of brain metastases. [2021]

13. Singapore pubmed.ncbi.nlm.nih.gov

Response and safety of whole-brain radiotherapy plus temozolomide for patients with brain metastases of non-small-cell lung cancer: A meta-analysis. [2022]

14. Cyprus pubmed.ncbi.nlm.nih.gov

Efficacy of synchronous stereotactic radiotherapy with temozolomide combined with whole brain radiotherapy in treating brain metastases originating from non-small cell lung cancer. [2021]

15. Ireland pubmed.ncbi.nlm.nih.gov

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy. [2023]