Berzosertib + Radiation for Triple-Negative Breast Cancer

Not currently recruiting at 14 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Chemotherapy, Prior RT, Uncontrolled illness, 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: 5

Duration: 5-6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates a new combination of treatments for certain types of breast cancer, using berzosertib (an experimental treatment) alongside radiation therapy. Berzosertib may stop tumor growth by blocking enzymes that cancer cells need, while radiation therapy uses high-energy rays to kill cancer cells. The trial aims to determine the best dose of berzosertib to use with radiation and assess if this combination is more effective than radiation alone. People with specific types of breast cancer that have not spread and who have undergone surgery might be suitable for this study. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you should avoid medications that strongly affect the enzyme CYP3A4, like certain antibiotics and herbal supplements, for 14 days before starting the trial. It's important to discuss your current medications with the trial team to ensure there are no interactions.

Is there any evidence suggesting that berzosertib and radiation therapy are likely to be safe for humans?

Research has shown that berzosertib, when combined with other cancer treatments, is generally well-tolerated. In earlier studies, patients with advanced tumors who received berzosertib alongside other drugs experienced some side effects, such as low levels of white blood cells (neutropenia), low levels of red blood cells (anemia), vomiting, and nausea. However, not all patients experienced these side effects, and they were mostly manageable.

In studies on various types of cancer, including lung cancer, berzosertib combined with other treatments was also well-tolerated. This indicates that while side effects can occur, they are usually not severe for most patients.

This trial is testing berzosertib with radiation therapy, a common cancer treatment. Since this trial is in the early stages (Phase 1), the main goal is to determine the best dose and ensure safety. This phase is designed to closely monitor any side effects that might occur. ^{1 2 3 4 5}

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

Researchers are excited about berzosertib combined with radiation therapy for triple-negative breast cancer because it represents a novel approach to tackling this aggressive cancer type. Unlike standard treatments, which often rely on chemotherapy, berzosertib is an ATR kinase inhibitor that works by specifically targeting and disrupting the cancer cells' ability to repair DNA damage. This unique mechanism makes it particularly promising when used alongside radiation therapy, which itself causes DNA damage to cancer cells. By preventing cancer cells from repairing radiation-induced damage, berzosertib could potentially enhance the effectiveness of radiation therapy, offering hope for improved outcomes in patients with this challenging condition.

What evidence suggests that berzosertib combined with radiation therapy might be an effective treatment for triple-negative breast cancer?

Research has shown that berzosertib, when combined with radiation therapy, might treat certain types of breast cancer more effectively. In this trial, participants will receive both berzosertib and radiation therapy. Berzosertib blocks specific enzymes that cancer cells require for growth. Earlier studies demonstrated promising results when berzosertib was combined with other treatments in patients with advanced solid tumors, including breast cancer. While detailed results for triple-negative breast cancer are still under investigation, using berzosertib with radiation directly targets tumor cells, potentially leading to better outcomes than radiation alone. Early trials suggested this method might help shrink or control cancer for longer periods. ^{1 2 3 6}

Who Is on the Research Team?

Robert W Mutter

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

Adults over 18 with certain types of breast cancer (triple-negative or hormone receptor-positive, HER2-negative) that didn't respond to chemotherapy can join. They must have completed surgery and possibly postoperative chemo recently, be in good health otherwise, and agree to use contraception. People with recent chemo, prior radiation in the same area, uncontrolled illnesses, or known hypersensitivity to similar drugs are excluded.

Inclusion Criteria

I had immediate reconstruction after my mastectomy.

My breast cancer is triple-negative or has low hormone receptor levels, and I've had specific chemotherapy.

I am not pregnant or able to become pregnant, and will use birth control during and after the study.

Exclusion Criteria

I have recovered from previous cancer treatment side effects, except for hair loss and mild nerve pain.

You had allergic reactions to drugs similar to berzosertib.

I have not had chemotherapy in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive berzosertib intravenously twice weekly and undergo radiation therapy 5 days a week for 5-6 weeks

5-6 weeks

5 visits per week (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Weekly visits (in-person)

Long-term Follow-up

Participants are followed up at 12 months, then yearly for up to 3 years to assess long-term outcomes

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Berzosertib
• Radiation Therapy

Trial Overview The trial is testing Berzosertib combined with standard radiation therapy against breast cancer that resisted chemotherapy. It aims to find the best dose of Berzosertib which blocks enzymes needed for cell growth and may enhance the effectiveness of radiation therapy.

How Is the Trial Designed?

Group I: Treatment (berzosertib, radiation therapy) Experimental Treatment 5 Interventions

Patients receive berzosertib IV over 60 minutes BIW for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo RT 5 days a week for 5-6 weeks depending on the type of surgery undergone. Patients also undergo a collection of blood on study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 of 658 patients with high-risk endometrial cancer, intensity-modulated radiation therapy (IMRT) was associated with significantly fewer grade ≥2 adverse events, such as diarrhea and hematologic issues, compared to 3-dimensional conformal radiation therapy (3DCRT) during follow-up.

IMRT also showed a trend towards fewer patient-reported symptoms like bowel urgency and abdominal cramps during treatment, indicating it may provide a better quality of life for patients undergoing radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation Therapy Techniques and Treatment-Related Toxicity in the PORTEC-3 Trial: Comparison of 3-Dimensional Conformal Radiation Therapy Versus Intensity-Modulated Radiation Therapy. Wortman, BG., Post, CCB., Powell, ME., et al.[2022]

Prostate cancer patients receiving image-guided radiotherapy (IGRT) experienced significantly less severe acute toxicity, such as urinary frequency, diarrhoea, and fatigue, compared to those who did not receive IGRT, with 23% vs 7% for urinary frequency ≥G3 and 15% vs 3% for diarrhoea ≥G2.

The onset of these toxicities was earlier in the non-IGRT group, indicating that IGRT not only reduces the severity of symptoms but also delays their onset, leading to a more tolerable treatment experience for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute toxicity in prostate cancer patients treated with and without image-guided radiotherapy. Gill, S., Thomas, J., Fox, C., et al.[2021]

In a study using various mouse models of triple negative breast cancer (TNBC), the combination of nintedanib (an antiangiogenic drug) and paclitaxel (PTX) showed enhanced antitumor efficacy in both primary and metastatic settings, indicating a potential new treatment strategy for TNBC.

The triple combination of nintedanib, PTX, and a PD-L1 antibody demonstrated optimal efficacy in advanced metastatic models, suggesting that this combination could improve treatment outcomes for patients with TNBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic impact of Nintedanib with paclitaxel and/or a PD-L1 antibody in preclinical models of orthotopic primary or metastatic triple negative breast cancer. Reguera-Nuñez, E., Xu, P., Chow, A., et al.[2023]

Image-guided Radiotherapy (IGRT) enhances the effectiveness of Intensity-Modulated Radiotherapy (IMRT) by addressing the challenges of organ and target motion in pelvic treatments, which is crucial for safely delivering higher doses to cervical cancer patients.

Implementing IGRT solutions is essential to minimize the risk of geographic miss targeting and overdose to organs at risk, thereby improving treatment outcomes and reducing toxicity in cervical cancer radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Problems and solutions in IGRT for cervical cancer. Ríos, I., Vásquez, I., Cuervo, E., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8991212/

Phase 1b study of berzosertib and cisplatin in patients with ... Platinum derivatives are commonly used for the treatment of patients with metastatic triple-negative breast cancer (TNBC).

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10969473/

Triple-Negative Breast Cancer and Emerging Therapeutic ... There is an ongoing Ib clinical trial testing the addition of berzosertib to radiation therapy for chemotherapy-resistant triple-negative and estrogen and/or ...

3. nature.com nature.com/articles/s41416-021-01405-x

Phase 1 study of the ATR inhibitor berzosertib (formerly ... Berzosertib + gemcitabine was well tolerated in patients with advanced solid tumours and showed preliminary efficacy signs.

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(20)37666-3/fulltext

Initial results of a phase 1 dose expansion cohort of M6620 ... Grade ≥3 related TEAEs occurred in 16/35 pts: neutropenia (n = 8), anemia (n = 5), vomiting (n = 4), nausea (n = 3), and 1 pt each with thrombocytopenia, ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0169500221006048

Lung Cancer Berzosertib plus gemcitabine was well tolerated in patients with advanced, pre-treated NSCLC. Based on the observed clinical efficacy, future clinical trials ...

6. aacrjournals.org aacrjournals.org/cancerres/article/78/4_Supplement/OT2-07-07/632040/Abstract-OT2-07-07-ATR-inhibitor-M6620-formerly-VX

Abstract OT2-07-07: ATR inhibitor M6620 (formerly VX-970 ... Grade ≥3 related treatment-emergent adverse events occurred in 16 of 35 patients: neutropenia (n=8), anemia (n=5), vomiting (n=4), nausea (n=3), ...