Radiation Therapy Followed by Intrathecal Trastuzumab/Pertuzumab in HER2+ Breast Leptomeningeal Disease

HER2-positive Breast Cancer Clinical Trial

Official title:

Phase I/II Study of Radiation Therapy Followed by Intrathecal Trastuzumab/Pertuzumab in the Management of HER2+ Breast Leptomeningeal Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04588545
• Other study ID #: MCC-20487
• Secondary ID: ML41590
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 10, 2020
• Est. completion date: November 1, 2024

Study information

• Verified date: May 2024
• Source: H. Lee Moffitt Cancer Center and Research Institute
• Contact: Kamran Ahmed, MD
• Phone: 813-745-8424
• Email: kamran.ahmed[@]moffitt.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of radiation therapy (RT) followed by intrathecal (IT) trastuzumab/pertuzumab in the management of HER2+ breast leptomeningeal disease (LMD). Treatment will be initiated with RT, whole brain RT (WBRT) and/or focal brain/spine RT followed by IT trastuzumab/pertuzumab.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 39
• Est. completion date: November 1, 2024
• Est. primary completion date: November 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Confirmation of HER2 positivity. All patients with HER2+ cancers will be allowed to enroll if they have leptomeningeal disease (LMD). Patients may be IHC 3+ and/or FISH-positive. IHC 2+ HER2 patients are eligible with reflex FISH-positive testing with the ratio =2.0.

And/or patients with HER2 positive cells in the cerebral spinal fluid.

• Participants may have concomitant brain metastases

• Cerebrospinal fluid (CSF) sampling is required to document LMD if not documented by MRI. Participants are still eligible CSF is negative but LMD disease is documented on MRI

• Life expectancy greater than 8 weeks

• Consent to pretreatment tumor biopsy or retrieval of archival tissue

• Normal renal (creatinine <1.5 × upper limit of normal [ULN]), liver (bilirubin < 1.5 × ULN, transaminases <3.0 × ULN, except in known hepatic disease, wherein may be <5 × ULN) and blood counts (white blood cells =2.5, neutrophils =1000, platelets =75,000, hemoglobin =8)

• LVEF >50%

• KPS >/= 60

• Patients with surgery within 14 days should have recovered from all effects of the surgery and be cleared by their surgeon

• There is no limit on prior systemic or IT therapies

• Must be willing to have an Ommaya reservoir placed and a candidate for an Ommaya reservoir placement

• Women of childbearing potential and sexually active males must commit to the use of effective contraception while on study. Contraception methods should start a minimum of 14 days before the first administration of study drug and continue for the duration of study treatment and for at least 7 months after the last dose of study treatment.

• Ability to sign informed consent.

• Patients may continue treatment with IV trastuzumab, pertuzumab, or other HER2-directed, hormonal, or chemotherapeutic agents if controlling systemic disease and leptomeningeal metastases that developed while on these therapies. In addition, at time of systemic progression, patients may start additional agents at the discretion of the treating physician according to criteria per protocol.

Exclusion Criteria:

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

• Cannot be on systemic agents (chemotherapy) that have Central Nervous System (CNS) penetration (temozolomide, carmustine, lomustine, etoposide, capecitabine, carboplatin, vinorelbine, bevacizumab, irinotecan, and topotecan) unless they develop or have progressive or persistent leptomeningeal metastases while on these agent(s). See protocol for additional information regarding systemic therapies.

• Major surgery or significant traumatic injury that has not been recovered from 14 days before the initiation of study drug

• Symptomatic lung disease resulting in shortness of breath at rest

• Women who are pregnant or breastfeeding

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

• Whole Body Radiation Therapy (WBRT) is not allowed while patients receive IT trastuzumab/pertuzumab; however, focal stereotactic or palliative RT is allowed

• Significant medical or psychiatric illness that would interfere with compliance and ability to tolerate treatment as outlined in the protocol

Related Conditions & MeSH terms

• HER2-positive Breast Cancer
• Leptomeningeal Disease
• Leptomeningeal Metastasis
• Meningeal Neoplasms

Intervention

Radiation:
• Radiation Therapy
Participants will receive radiation therapy (RT), either whole brain radiation therapy or focal brain/spine RT. The goal of RT is to palliate symptoms and improve the flow of Intrathecal (IT) therapy through the cerebrospinal fluid (CSF). As such, various RT schedules and targets are permitted. It is expected that the majority of patients will receive WBRT with 30 Gy in 10 fractions. However, shorter fractions of 20 Gy in 5 fractions of WBRT are permitted. In those patients who have more localized leptomeningeal disease in the spine, focal RT in up to 10 fractions may be administered with the exact dose left up to the discretion of the treating radiation oncologist.

Drug:
• Pertuzumab
Participants will be treated at 1 of 4 dose levels of pertuzumab, beginning at 10 mg and increasing up to 80 mg or Maximum Tolerated Dose (MTD).
• Trastuzumab
Participants will be treated at a fixed dose of 80 mg trastuzumab.

Locations

Country	Name	City	State
United States	Northwestern University	Evanston	Illinois
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
H. Lee Moffitt Cancer Center and Research Institute	Genentech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1: Maximum Tolerated Dose (MTD) of Intrathecal (IT) pertuzumab in combination with IT trastuzumab	MTD will be determined by testing increasing doses or pertuzumab beginning at 10 mg increasing to 20 mg, 40 mg and 80 mg, along with a fixed dose of 80 mg Trastuzumab.	Up to 12 weeks per dosing cohort
Primary	Phase 2: Overall Survival (OS)	1 year Overall Survival (OS), defined as the time between the date of study enrollment and the date of death due to any cause.	1 year after study enrollment
Secondary	Response Rate	All patients included in the study will be assessed for response to treatment. Each patient will be assigned one of the following categories: 1) Complete Response,2) Partial Response, 3) Stable Disease, 4) Progressive Disease, 5) Early death due to disease, 6) Early death due to toxicity 7)Early death due to unknown cause. Participants in categories 4 through 6 would be considered as failing to respond to treatment.	Up to 1 year
Secondary	Progression Free Survival (PFS)	PFS measured from the date of first treatment to the date of first observation of Progressive Disease (PD), nonreversible neurologic progression, or death due to any cause	Up to 1 year

External Links

•   Moffitt Cancer Center's Clinical Trials Website