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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
Sponsored by
H. Lee Moffitt Cancer Center and Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

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

Experimental

Experimental

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

First Posted
October 7, 2020
Last Updated
October 17, 2023
Sponsor
H. Lee Moffitt Cancer Center and Research Institute
Collaborators
Genentech, Inc.
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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
No
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
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.
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
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.
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
No
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
Email
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
Email
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
Email
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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