AZD1390 + SBRT for Metastatic Cancer

Not currently recruiting at 4 trial locations

Overseen By David Guttmann, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Brain metastases, ILD, Cardiac dysfunction, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining AZD1390, a new drug, with stereotactic body radiation therapy (SBRT) safely treats individuals with metastatic solid tumor cancer. The study examines different groups based on cancer spread, such as to the lungs or bowel, and tests various doses to identify the most effective. This trial may suit individuals with cancer that has metastasized and who qualify for SBRT. As a Phase 1 trial, the research focuses on understanding the treatment's effects in people, offering participants the chance to be among the first to receive this new drug.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications. However, you cannot take strong inhibitors or inducers of CYP3A4 within 2 weeks before starting AZD1390, and you should avoid certain medications like prazosin, cimetidine, simvastatin, dofetilide, metformin, dabigatran, digoxin, and fexofenadine while on the study.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you should avoid certain drugs like strong inhibitors or inducers of CYP3A4 and sensitive substrates of BCRP, OATP1B1, MATE1, MATE2K, and P-gp. It's best to discuss your current medications with the study team to see if any adjustments are needed.

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

A previous study found that the drug AZD1390, when combined with radiation therapy, showed promise in treating brain tumors. This combination was generally safe, and researchers identified the highest tolerable dose. Some side effects occurred, but they were manageable. Studies also show that AZD1390 can effectively target brain tumors.

Research indicates that stereotactic body radiotherapy (SBRT) is safe and well-tolerated for treating cancers that have spread to a few areas. It has a good safety record, with few severe side effects reported. Overall, the combination of AZD1390 and SBRT has shown potential for safe use in targeting cancers that have spread, with careful monitoring. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of AZD1390 and Stereotactic Body Radiotherapy (SBRT) for treating metastatic cancer because it offers a novel approach. Unlike traditional chemotherapy and radiation treatments, AZD1390 is a cutting-edge drug that specifically targets the DNA damage response, potentially enhancing the effects of radiation on tumors. SBRT, on the other hand, delivers high doses of radiation precisely to cancer sites, minimizing harm to surrounding healthy tissues. This combination aims to improve the effectiveness and precision of cancer treatment, offering hope for better outcomes in patients with challenging metastatic conditions.

What evidence suggests that this trial's treatments could be effective for metastatic cancer?

Research shows that AZD1390, a treatment studied in this trial, holds promise as a radiosensitizer, enhancing cancer cells' responsiveness to radiation therapy. Previous studies have found it effective in boosting treatments for conditions like breast cancer and brain tumors. For instance, in patients with glioblastoma (a type of brain cancer), AZD1390 combined with radiation therapy resulted in an encouraging average survival time of 12.7 months. Additionally, stereotactic body radiotherapy (SBRT), another treatment tested in this trial, has a strong track record in treating various cancers. It has demonstrated high success rates, with 88% of spinal metastases controlled and most patients experiencing symptom relief. Together, these treatments in this trial offer a potentially stronger approach to combating metastatic cancers. ^{1 2 3 6 7}

Who Is on the Research Team?

Daniel Higginson, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

Adults with confirmed metastatic solid tumor cancer, suitable for SBRT treatment to two disease sites, and meeting specific health criteria (e.g., adequate blood counts, liver function). Must not be pregnant or breastfeeding and willing to use contraception. Excludes those with severe medical conditions, brain metastases treatments ongoing, recent heart issues, certain lung diseases, high risk of heart rhythm problems.

Inclusion Criteria

My cancer has spread, as shown by scans. A biopsy to confirm this was preferred but not mandatory.

Willing and able to provide written informed consent

I am eligible for a specific radiation therapy targeting 2 cancer sites.

Exclusion Criteria

I haven't taken strong CYP3A4 inhibitors or inducers in the last 2 weeks.

I have had lung inflammation or damage that needed steroids.

I have had serious lung infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AZD1390 in combination with stereotactic body radiation therapy (SBRT) to assess safety and tolerability

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AZD1390
• Stereotactic Body Radiotherapy

Trial Overview The trial is testing the safety of a new drug called AZD1390 when given alongside Stereotactic Body Radiotherapy (SBRT) in adults with various types of advanced cancers that have spread to other parts of the body.

How Is the Trial Designed?

Group I: Arm B, Dose Level 4 Experimental Treatment 2 Interventions

Participants have peripheral metastasis with bowel and lung in SBRT treatment planning target

Group II: Arm B, Dose Level 3 Experimental Treatment 2 Interventions

Participants have peripheral metastasis with bowel and lung in SBRT treatment planning target

Group III: Arm B, Dose Level 2 Experimental Treatment 2 Interventions

Participants have peripheral metastasis with bowel and lung in SBRT treatment planning target

Group IV: Arm B, Dose Level 1 Experimental Treatment 2 Interventions

Participants have peripheral metastasis with bowel and lung in SBRT treatment planning target

Group V: Arm A, Dose Level 4 Experimental Treatment 2 Interventions

Participants have peripheral metastases only, without bowel and lung in SBRT treatment planning target. Once 2 dosing cohorts of safety data are available from concomitant dosing of AZD1390 with SBRT in Arm A, and provided that Arm A is advancing to Cohort 3, Arm B (with bowel and lung in SBRT treatment planning target \[PTV\]) may be triggered at the initial dose level).

Group VI: Arm A, Dose Level 3 Experimental Treatment 2 Interventions

Participants have peripheral metastases only, without bowel and lung in SBRT treatment planning target. Once 2 dosing cohorts of safety data are available from concomitant dosing of AZD1390 with SBRT in Arm A, and provided that Arm A is advancing to Cohort 3, Arm B (with bowel and lung in SBRT treatment planning target \[PTV\]) may be triggered at the initial dose level).

Group VII: Arm A, Dose Level 2 Experimental Treatment 2 Interventions

Participants have peripheral metastases only, without bowel and lung in SBRT treatment planning target. Once 2 dosing cohorts of safety data are available from concomitant dosing of AZD1390 with SBRT in Arm A, and provided that Arm A is advancing to Cohort 3, Arm B (with bowel and lung in SBRT treatment planning target \[PTV\]) may be triggered at the initial dose level).

Group VIII: Arm A, Dose Level 1 Experimental Treatment 2 Interventions

Participants have peripheral metastases only, without bowel and lung in SBRT treatment planning target. Once 2 dosing cohorts of safety data are available from concomitant dosing of AZD1390 with SBRT in Arm A, and provided that Arm A is advancing to Cohort 3, Arm B (with bowel and lung in SBRT treatment planning target \[PTV\]) may be triggered at the initial dose level).

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

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

Published Research Related to This Trial

Stereotactic body radiotherapy (SBRT) for spinal metastases demonstrated high efficacy, achieving an overall pain response rate of 83% and a 1-year local control rate of 94% across 69 studies involving 5736 patients.

SBRT was found to be safe, with a low vertebral fracture rate of 9% and no reported cases of radiation-induced myelopathy, indicating it provides effective pain and disease control with minimal risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of SBRT for spine metastases: A systematic review and meta-analysis for preparation of an ESTRO practice guideline. Guninski, RS., Cuccia, F., Alongi, F., et al.[2023]

Stereotactic body radiotherapy (SBRT) demonstrated high local control rates for spinal metastasis, with 83% at 1 year and 71% at 2 years, and a median overall survival of 30.6 months among 26 patients with 32 lesions.

The treatment was found to be safe, with only 16% of patients experiencing acute pain flare, which was manageable, and no cases of radiation-induced myelopathy reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic body radiotherapy as a primary treatment for spinal metastasis: a single institution experience. Yeung, WME.[2021]

Stereotactic body radiation therapy (SBRT) significantly reduces the risk of local failure and the need for reirradiation in patients with spinal metastases compared to conventional external beam radiation therapy (cEBRT), with local failure rates at 24 months being 14.8% for SBRT versus 35.6% for cEBRT (P < .001).

While SBRT has a lower reirradiation rate (2.2% at 1 year) compared to cEBRT (15.8% at 1 year), it is associated with a higher incidence of grade 3 vertebral compression fractures, indicating a need for careful monitoring of this adverse effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mature Local Control and Reirradiation Rates Comparing Spine Stereotactic Body Radiation Therapy With Conventional Palliative External Beam Radiation Therapy. Zeng, KL., Myrehaug, S., Soliman, H., et al.[2022]

This multicenter randomized phase III trial aims to determine if combining Stereotactic Body Radiation Therapy (SBRT) with standard systemic treatment improves progression-free survival in patients with solid tumors and up to 3 bone-only metastases, with a total of 196 patients expected to be enrolled over 4 years.

The primary goal is to assess progression-free survival at 1 year, while secondary outcomes will evaluate local control, cancer-specific survival, quality of life, and pain management, highlighting the potential for SBRT to enhance patient outcomes by controlling bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of extracranial stereotactic body radiation therapy (SBRT) added to standard treatment in patients with solid tumors (breast, prostate and non-small cell lung cancer) with up to 3 bone-only metastases: study protocol for a randomised phase III trial (STEREO-OS). Thureau, S., Marchesi, V., Vieillard, MH., et al.[2021]

High-dose stereotactic body radiation therapy (SBRT) demonstrated a 100% local control rate at one year and 96% at two years for patients with one to three lung metastases, indicating its efficacy in managing these tumors.

The treatment was well-tolerated, with only 8% of patients experiencing grade 3 toxicity and no grade 4 toxicity reported, suggesting a favorable safety profile for high-dose SBRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. Rusthoven, KE., Kavanagh, BD., Burri, SH., et al.[2022]

Stereotactic body radiotherapy (SBRT) for localized renal cell carcinoma (RCC) was well-tolerated in 19 patients aged 59-89, with no dose-limiting toxicities observed at doses up to 48Gy in 4 fractions.

Among the patients treated, 3 showed a partial response and 12 had stable disease, indicating that SBRT can be an effective treatment option for patients who are poor surgical candidates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose-escalation study of stereotactic body radiotherapy (SBRT) for poor surgical candidates with localized renal cell carcinoma. Ponsky, L., Lo, SS., Zhang, Y., et al.[2022]

Stereotactic body radiotherapy (SBRT) is increasingly used to treat spinal bone metastases, which are common in cancer patients, and can provide long-lasting relief and potential curative outcomes in select cases.

In particular, SBRT may be beneficial for oligometastatic patients or those with a longer life expectancy, shifting the focus from purely palliative care to a more therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spinal metastases: Is stereotactic body radiation therapy supported by evidences? De Bari, B., Alongi, F., Mortellaro, G., et al.[2022]

Stereotactic ablative radiotherapy (SABR) demonstrated a high local control rate of 91.2% for skeletal metastases in a study of 22 patients, with a median follow-up of 15.6 months, indicating its effectiveness in managing oligometastatic and oligoprogressive diseases.

The treatment resulted in significant pain control for two-thirds of symptomatic patients, with limited toxicities reported, including only two vertebral fractures and one case of grade 3 esophagitis, suggesting that SABR is a safe option for patients with skeletal metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilization of stereotactic ablative radiotherapy in oligometastatic & oligoprogressive skeletal metastases: Results and pattern of failure. Kam, TY., Chan, OSH., Hung, AWM., et al.[2019]

In a study of 84 patients with spinal metastases treated with stereotactic body radiotherapy (SBRT), targeting only the lesion (LO) showed similar tumor control and pain reduction compared to targeting the full vertebral body (FVB), indicating that LO may be a sufficient treatment approach.

There were no significant differences in the rates of compression fractures between the LO and FVB groups, suggesting that both treatment strategies are equally safe in terms of fracture risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Clinical Outcomes Stratified by Target Delineation for Patients Undergoing Stereotactic Body Radiotherapy for Spinal Metastases. Attiah, M., Sandler, K., Medina, R., et al.[2020]

In a study of 46 patients treated with spine stereotactic body radiation therapy (SBRT), no cases of myelopathy were reported, suggesting that current guidelines may overestimate the risk of this complication, even when exceeding recommended dose limits.

The most common side effects observed were pain and nausea, with specific dose thresholds identified: a maximum dose to the spinal cord of 38.5 Gy and to the thecal sac of 67.7 Gy, indicating that higher doses may be tolerated without severe toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosimetric analysis of varying cord planning organ at risk volume in spine stereotactic body radiation therapy. Owen, D., Mayo, CS., Song, L., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10618650/

ATM-Inhibitor AZD1390 Is a Radiosensitizer for Breast Cancer ... Our results demonstrate that AZD1390 effectively sensitizes breast cancer CM to radiation therapy in DDR mutant tumors. This study demonstrates the potential ...

2. 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.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03423628

A Study to Assess the Safety and Tolerability of AZD1390 ... 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 ...

4. cancernetwork.com cancernetwork.com/view/azd1390-radiation-yields-encouraging-efficacy-safety-in-glioblastoma

AZD1390/Radiation Yields Encouraging Efficacy, Safety in ... Among 21 patients who received tolerated doses of AZD1390 in combination with radiation, the median overall survival (OS) was 12.7 months (95% ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0014482724004737

AZD1390, an Ataxia telangiectasia mutated inhibitor ... The study aimed to evaluate the potential anti-cancer effects of AZD1390, a key component of the DNA damage response, in breast cancer cells.

6. astrazenecaclinicaltrials.com astrazenecaclinicaltrials.com/study/D6940C00002

A study to assess the safety and tolerability of AZD1390 ... This study will test an investigational drug called AZD1390 in combination with radiation therapy for the treatment of brain tumors.

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

Safety and Preliminary Efficacy of AZD1390 + Radiation ... The maximum tolerated dose was identified as 400 mg in Arm A and 300 mg in Arm C. Dose limiting toxicities included, but were not limited to, ...