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

Recruiting at 1 trial location

Overseen By Fiona Roberts, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining radiation therapy with two medications, trastuzumab and pertuzumab, can safely improve survival for individuals with HER2-positive breast cancer that has spread to the leptomeninges, the protective layers around the brain and spinal cord. Participants will first receive radiation, followed by varying doses of the medications to determine the safest and most effective treatment plan. This trial may suit those diagnosed with HER2-positive breast cancer that has spread to the brain or spinal fluid and who are willing to undergo specific procedures like Ommaya reservoir placement, a small device used for delivering medication directly to the brain. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

Studies have shown that trastuzumab and pertuzumab, when combined with chemotherapy, improve survival rates in patients. Research indicates that administering trastuzumab directly into the spinal fluid is well-tolerated and may enhance overall survival for patients with HER2-positive breast cancer. However, this study remains in its early stages, focusing on the safety of these treatments when combined with radiation. Although these treatments are approved for other uses, the current study aims to provide more specific safety data for this combination in treating breast cancer that has spread to the membranes around the brain and spinal cord. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for leptomeningeal metastasis from breast cancer because they combine radiation therapy with a targeted approach using pertuzumab and trastuzumab. Unlike standard treatments, which often involve systemic chemotherapy, this approach directly delivers the drugs via an Ommaya reservoir, potentially improving drug delivery to the brain and spinal cord. Pertuzumab and trastuzumab target the HER2 protein, which is overexpressed in some breast cancers, aiming to more effectively halt cancer growth. The different dosing levels of pertuzumab in the study allow researchers to explore optimal dosages for safety and effectiveness. This targeted method could offer a more precise and potentially less toxic treatment compared to conventional options.

What evidence suggests that this trial's treatments could be effective for leptomeningeal metastasis from breast cancer?

Studies have shown that radiation therapy is an important tool for treating leptomeningeal disease in breast cancer, helping some patients live longer. In this trial, participants will receive radiation therapy followed by varying doses of trastuzumab and pertuzumab. These targeted treatments have shown promise for HER2-positive breast cancer. Administering trastuzumab directly into the spinal fluid has improved or stabilized the condition in many cases. Combining pertuzumab with trastuzumab has led to significant improvements, helping patients live longer and better. Overall, this combination of treatments shows potential for improving outcomes in leptomeningeal metastasis from breast cancer. ^{5 6 7 8 9}

Who Is on the Research Team?

Kamran Ahmed, M.D.

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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 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]

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]

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]

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]

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]

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]

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 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]

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