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

Primary Purpose

HER2-positive Breast Cancer, Leptomeningeal Metastasis, Leptomeningeal Disease

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Radiation Therapy

Pertuzumab

Trastuzumab

About this trial

This is an interventional treatment trial for HER2-positive Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Moffitt Cancer CenterRecruiting
Northwestern UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Radiation Therapy followed by 10 mg Pertuzumab and 80 mg Trastuzumab

Radiation Therapy followed by 20 mg Pertuzumab and 80 mg Trastuzumab

Radiation Therapy followed by 40 mg Pertuzumab and 80 mg Trastuzumab

Radiation Therapy followed by 80 mg Pertuzumab and 80 mg Trastuzumab

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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.

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

Full Information

NCT ID

NCT04588545

First Posted

October 7, 2020

Last Updated

October 17, 2023

Sponsor

H. Lee Moffitt Cancer Center and Research Institute

Collaborators

Genentech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT04588545

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

December 10, 2020 (Actual)

Primary Completion Date

November 1, 2024 (Anticipated)

Study Completion Date

November 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

H. Lee Moffitt Cancer Center and Research Institute

Collaborators

Genentech, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HER2-positive Breast Cancer, Leptomeningeal Metastasis, Leptomeningeal Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

39 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Radiation Therapy followed by 10 mg Pertuzumab and 80 mg Trastuzumab

Arm Type

Experimental

Arm Description

Arm Title

Radiation Therapy followed by 20 mg Pertuzumab and 80 mg Trastuzumab

Arm Type

Experimental

Arm Description

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.

Arm Title

Radiation Therapy followed by 40 mg Pertuzumab and 80 mg Trastuzumab

Arm Type

Experimental

Arm Description

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.

Arm Title

Radiation Therapy followed by 80 mg Pertuzumab and 80 mg Trastuzumab

Arm Type

Experimental

Arm Description

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.

Intervention Type

Radiation

Intervention Name(s)

Radiation Therapy

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Pertuzumab

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

Trastuzumab

Intervention Description

Participants will be treated at a fixed dose of 80 mg trastuzumab.

Primary Outcome Measure Information:

Title

Phase 1: Maximum Tolerated Dose (MTD) of Intrathecal (IT) pertuzumab in combination with IT trastuzumab

Description

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.

Time Frame

Up to 12 weeks per dosing cohort

Title

Phase 2: Overall Survival (OS)

Description

1 year Overall Survival (OS), defined as the time between the date of study enrollment and the date of death due to any cause.

Time Frame

1 year after study enrollment

Secondary Outcome Measure Information:

Title

Response Rate

Description

Time Frame

Up to 1 year

Title

Progression Free Survival (PFS)

Description

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

Time Frame

Up to 1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Kamran Ahmed, MD

Phone

813-745-8424

kamran.ahmed@moffitt.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kamran Ahmed, MD

Organizational Affiliation

Moffitt Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

Moffitt Cancer Center

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Michelle DeJesus

Phone

813-745-6911

Michelle.DeJesus@moffitt.org

First Name & Middle Initial & Last Name & Degree

Kamran Ahmed, MD

First Name & Middle Initial & Last Name & Degree

Peter Forsyth, MD

First Name & Middle Initial & Last Name & Degree

Avan Armaghani, MD

First Name & Middle Initial & Last Name & Degree

Ricardo Costa, MD, MSc

First Name & Middle Initial & Last Name & Degree

Arnold Etame, MD, PhD

First Name & Middle Initial & Last Name & Degree

Heather Han, MD

First Name & Middle Initial & Last Name & Degree

Hung Khong, MD

First Name & Middle Initial & Last Name & Degree

James Liu, MD

First Name & Middle Initial & Last Name & Degree

Loretta Loftus, MD, MBA

First Name & Middle Initial & Last Name & Degree

Sepideh Mokhtari, MD

First Name & Middle Initial & Last Name & Degree

Solmaz Sahebjam, MD

First Name & Middle Initial & Last Name & Degree

Hatem Soliman, MD

First Name & Middle Initial & Last Name & Degree

Nam Tran, MD, PhD

First Name & Middle Initial & Last Name & Degree

Michael Votgelbaum, MD, PhD

First Name & Middle Initial & Last Name & Degree

Michael Yu, MD

Facility Name

Northwestern University

City

Evanston

State/Province

Illinois

ZIP/Postal Code

60208

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Priya Kumthekar, MD

Phone

312-695-4360

priya.kumthekar@nm.org

First Name & Middle Initial & Last Name & Degree

Priya Kumthekar, MD

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Links:

URL

https://moffitt.org/clinical-trials-research/clinical-trials/

Description

Moffitt Cancer Center's Clinical Trials Website

Learn more about this trial

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

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