Radiation + HER2-targeted Therapy for Leptomeningeal Metastasis from Breast Cancer

Recruiting at 1 trial location

Overseen By Kamran Ahmed, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: CNS-penetrating chemotherapy

Disqualifiers: Pregnancy, Symptomatic lung disease, 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: 4

39 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out if radiation therapy followed by intrathecal trastuzumab and pertuzumab is safe and will result in improved survival in HER2 positive breast cancer which has metastasized to the leptomeninges.

Will I have to stop taking my current medications?

You may need to stop taking certain medications, especially those that affect the central nervous system, unless your condition worsened while on them. However, you can continue with some HER2-targeted therapies if they are controlling your disease.

What data supports the effectiveness of this treatment for leptomeningeal metastasis from breast cancer?

Research shows that stereotactic radiosurgery, a type of precise radiation therapy, has been effective in controlling leptomeningeal metastasis in breast cancer patients, providing durable intracranial control. Additionally, systemic therapies and targeted agents like trastuzumab have shown promise in improving outcomes for patients with brain metastasis, which may be relevant for leptomeningeal metastasis treatment. ^{1 2 3 4 5}

Is radiation therapy generally safe for humans?

Radiation therapy techniques like Intensity-Modulated Radiation Therapy (IMRT) and Image-Guided Radiation Therapy (IGRT) have been shown to improve safety by better targeting cancer cells and sparing normal tissues, reducing side effects. Proton therapy and surgically targeted radiation therapy have also been evaluated for safety, with studies indicating they are generally safe for treating various cancers, including brain and prostate cancers. ^{6 7 8 9 10}

How is the treatment of Radiation + HER2-targeted Therapy for Leptomeningeal Metastasis from Breast Cancer different from other treatments?

This treatment is unique because it combines radiation therapy with HER2-targeted therapy, which is specifically designed to target and treat HER2-positive breast cancer cells that have spread to the leptomeninges (the membranes surrounding the brain and spinal cord). This approach aims to improve outcomes by addressing both the cancer cells and the specific genetic characteristics of the tumor, offering a more tailored treatment compared to traditional methods. ^{1 4 11 12 13}

Research Team

Kamran Ahmed, M.D.

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for individuals with HER2 positive breast cancer that has spread to the lining of the brain and spine. Participants must have a life expectancy over 8 weeks, normal organ function, and be able to undergo certain procedures like CSF sampling. Pregnant women or those with serious reactions to study drugs, significant lung disease, or recent major surgery cannot join.

Inclusion Criteria

I have recovered from surgery within the last 14 days and my surgeon has cleared me.

I have had any number of previous treatments.

Commitment to effective contraception for sexually active individuals

Exclusion Criteria

History of serious adverse event to any of the study drugs or study drug components

Current or prior participation in a study of an investigational agent or investigational device within 2 weeks of the first dose of study treatment

I experience shortness of breath even when I am resting.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation Therapy

Participants receive whole brain or focal brain/spine radiation therapy

4 weeks

Twice a week

Intrathecal Treatment

Participants receive intrathecal trastuzumab and pertuzumab via Ommaya reservoir

12 weeks

Twice a week for 4 weeks, once a week for 4 weeks, then once every 2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Treatment Details

Interventions

• Pertuzumab
• Radiation Therapy
• Trastuzumab

Trial Overview The study tests if radiation therapy followed by intrathecal (directly into the spinal canal) trastuzumab and pertuzumab improves survival in patients whose breast cancer has spread to their leptomeninges. It checks for safety and effectiveness of this treatment sequence.

Participant Groups

Group I: Radiation Therapy followed by 80 mg Pertuzumab and 80 mg Trastuzumab Experimental Treatment 3 Interventions

Treatment will be initiated with radiation therapy (RT), either whole brain radiation therapy or focal brain/spine radiation therapy. Participants will be treated at dose level 4 of 4 with 80 mg pertuzumab along with 80 mg trastuzumab via Ommaya reservoir over 2-5 minutes. Pertuzumab and trastuzumab will be administered sequentially. Participants will be observed 30 to 60 minutes before commencing the next agent. Participants will be treated twice a week for 4 weeks, once a week for 4 weeks, and then once every 2 weeks.

Group II: Radiation Therapy followed by 40 mg Pertuzumab and 80 mg Trastuzumab Experimental Treatment 3 Interventions

Treatment will be initiated with radiation therapy (RT), either whole brain radiation therapy or focal brain/spine radiation therapy. Participants will be treated at dose level 3 of 4 with 40 mg pertuzumab along with 80 mg trastuzumab via Ommaya reservoir over 2-5 minutes. Pertuzumab and trastuzumab will be administered sequentially. Participants will be observed 30 to 60 minutes before commencing the next agent. Participants will be treated twice a week for 4 weeks, once a week for 4 weeks, and then once every 2 weeks.

Group III: Radiation Therapy followed by 20 mg Pertuzumab and 80 mg Trastuzumab Experimental Treatment 3 Interventions

Treatment will be initiated with radiation therapy (RT), either whole brain radiation therapy or focal brain/spine radiation therapy. Participants will be treated at dose level 2 of 4 with 20 mg pertuzumab along with 80 mg trastuzumab via Ommaya reservoir over 2-5 minutes. Pertuzumab and trastuzumab will be administered sequentially. Participants will be observed 30 to 60 minutes before commencing the next agent. Participants will be treated twice a week for 4 weeks, once a week for 4 weeks, and then once every 2 weeks.

Group IV: Radiation Therapy followed by 10 mg Pertuzumab and 80 mg Trastuzumab Experimental Treatment 3 Interventions

Treatment will be initiated with radiation therapy (RT), either whole brain radiation therapy or focal brain/spine radiation therapy. Participants will be treated at dose level 1 of 4 with 10 mg pertuzumab along with 80 mg trastuzumab via Ommaya reservoir over 2-5 minutes. Pertuzumab and trastuzumab will be administered sequentially. Participants will be observed 30 to 60 minutes before commencing the next agent. Participants will be treated twice a week for 4 weeks, once a week for 4 weeks, and then once every 2 weeks.

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?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

A novel treatment approach combining frameless stereotactic radiosurgery and intrathecal chemotherapy was successfully used for a patient with bulky leptomeningeal relapse of breast cancer, avoiding the toxicities associated with repeat whole brain radiation.

The patient showed an excellent response to this treatment, achieving durable control of intracranial disease, highlighting the potential efficacy of this strategy in similar clinical situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic Radiosurgery as Part of Multimodal Treatment in a Bulky Leptomeningeal Recurrence of Breast Cancer. Bertke, MH., Burton, EC., Shaughnessy, JN.[2020]

Craniospinal irradiation using helical tomotherapy (HT-CSI) showed some effectiveness in symptom palliation for patients with leptomeningeal metastasis (LM), particularly benefiting 67% of breast cancer patients, although overall survival rates remained low with a median survival of only 2 to 6 months depending on cancer type.

The treatment was associated with various acute toxicities, including hematological issues and fatigue, highlighting the need for careful management of side effects while providing palliative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Helical tomotherapy in patients with leptomeningeal metastases. Schiopu, SR., Habl, G., Haefner, M., et al.[2022]

In a randomized phase II trial involving 63 patients with leptomeningeal metastasis from solid tumors, proton craniospinal irradiation (pCSI) significantly improved central nervous system progression-free survival (CNS PFS) compared to photon involved-field radiotherapy (IFRT), with median CNS PFS of 7.5 months for pCSI versus 2.3 months for IFRT.

pCSI also demonstrated a benefit in overall survival (OS), with a median OS of 9.9 months compared to 6.0 months for IFRT, while maintaining a similar rate of serious treatment-related adverse events, indicating its safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Phase II Trial of Proton Craniospinal Irradiation Versus Photon Involved-Field Radiotherapy for Patients With Solid Tumor Leptomeningeal Metastasis. Yang, JT., Wijetunga, NA., Pentsova, E., et al.[2023]

A recent phase III trial showed that adding intrathecal liposomal cytarabine to systemic treatment significantly improves progression-free survival in patients with breast cancer and newly diagnosed leptomeningeal metastasis.

The treatment approach for leptomeningeal metastasis should be individualized, combining various therapies like intrathecal pharmacotherapy, systemic treatments, and focal radiotherapy based on the patient's specific cancer characteristics and previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How we treat patients with leptomeningeal metastases. Le Rhun, E., Preusser, M., van den Bent, M., et al.[2021]

CNS metastasis in breast cancer patients is becoming more common, likely due to better systemic therapies, but standard treatments like whole-brain radiation do not improve survival, only symptom control.

For single brain metastases, surgery or radiosurgery is preferred, while intrathecal chemotherapy is used for leptomeningeal metastasis, though its effectiveness is mainly for short-term symptom relief.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CNS metastasis in primary breast cancer. Sharma, M., Abraham, J.[2007]

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]

In a study of 29 patients with gynecologic cancers who underwent reirradiation using intensity modulated proton therapy (IMPT), the 1-year local control rate was 83.5% and overall survival was 65.7%, indicating effective treatment outcomes.

The study reported a low incidence of severe toxicity, with only 10% of patients experiencing grade 3 toxicity and a high 1-year freedom from late grade 3+ toxicity rate of 96.3%, suggesting that IMPT is a safe option for re-RT in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Outcomes of Intensity Modulated Proton Therapy Reirradiation for Gynecologic Malignancies. Pollock, AE., Risher, H., Berger, M., et al.[2023]

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 27,647 Medicare beneficiaries with prostate cancer, proton radiotherapy (PRT) was associated with lower genitourinary toxicity at 6 months compared to intensity-modulated radiotherapy (IMRT), but this difference disappeared by 12 months post-treatment.

PRT was significantly more expensive than IMRT, with median Medicare reimbursements of $32,428 for PRT compared to $18,575 for IMRT, yet no long-term differences in toxicity were observed between the two treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. Yu, JB., Soulos, PR., Herrin, J., et al.[2022]

GammaTile® Surgically Targeted Radiation Therapy (STaRT) offers a novel approach to brain tumor treatment by using a bioresorbable tile that delivers radiation while minimizing direct contact with brain tissue, which helps reduce normal brain toxicity.

This therapy has been FDA approved since 2018 for recurrent brain tumors and expanded in 2020 to include newly-diagnosed malignant tumors, with ongoing trials aimed at comparing its efficacy and safety against standard radiation treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgically targeted radiation therapy (STaRT) trials for brain neoplasms: A comprehensive review. Odia, Y., Gutierrez, AN., Kotecha, R.[2023]

A systematic review of 208 patients with HER2+ breast cancer and leptomeningeal metastases found that intrathecal administration of HER2-targeted therapies did not provide any additional survival benefits compared to oral or intravenous treatments.

Trastuzumab-deruxtecan showed potential for improved overall survival compared to other HER2-targeted therapies, suggesting it may be a promising option for future studies despite the small patient cohort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases. Lazaratos, AM., Maritan, SM., Quaiattini, A., et al.[2023]

In a study of 82 patients with HER2+ breast cancer and leptomeningeal metastases, overall survival was found to be 8.3 months, with 1-year and 2-year survival rates at 42% and 21%, respectively.

Patients who received radiotherapy and those without neurological symptoms had significantly longer survival, highlighting the importance of multimodal treatment strategies, including targeted therapy and chemotherapy, in improving outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leptomeningeal metastases in patients with human epidermal growth factor receptor 2 positive breast cancer: Real-world data from a multicentric European cohort. Ratosa, I., Dobnikar, N., Bottosso, M., et al.[2022]

Up to 55% of patients with HER2-positive breast cancer develop CNS metastases, leading to various neurological symptoms, highlighting the need for effective treatment strategies.

Recent advancements in systemic therapies, such as tucatinib and trastuzumab-deruxtecan, along with ongoing clinical trials, offer hope for improved outcomes in patients with CNS metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modern Management and Diagnostics in HER2+ Breast Cancer with CNS Metastasis. Warrior, S., Cohen-Nowak, A., Kumthekar, P.[2023]

References

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

Stereotactic Radiosurgery as Part of Multimodal Treatment in a Bulky Leptomeningeal Recurrence of Breast Cancer. [2020]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Helical tomotherapy in patients with leptomeningeal metastases. [2022]

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

Randomized Phase II Trial of Proton Craniospinal Irradiation Versus Photon Involved-Field Radiotherapy for Patients With Solid Tumor Leptomeningeal Metastasis. [2023]

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

How we treat patients with leptomeningeal metastases. [2021]

5. England pubmed.ncbi.nlm.nih.gov

CNS metastasis in primary breast cancer. [2007]

6. United States 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. [2022]

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

Clinical Outcomes of Intensity Modulated Proton Therapy Reirradiation for Gynecologic Malignancies. [2023]

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

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

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

Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Surgically targeted radiation therapy (STaRT) trials for brain neoplasms: A comprehensive review. [2023]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases. [2023]

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

Leptomeningeal metastases in patients with human epidermal growth factor receptor 2 positive breast cancer: Real-world data from a multicentric European cohort. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Modern Management and Diagnostics in HER2+ Breast Cancer with CNS Metastasis. [2023]