Breast CancerPhase 1/2NCT01325207

Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer

A Phase 1/2 study testing Trastuzumab in people with Breast Cancer, run by Northwestern University at 8 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The drug being studied is Trastuzumab, a medicine that is used to slow or stop the growth of cancerous tumors that are HER-2 positive. Patients are being asked to participate in this study because they have been diagnosed with having tumor cells in their spinal fluid. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Breast Cancer
What is being tested?: Trastuzumab
Type of treatment: Injection or infusion, Surgery or procedure
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 34 participants
Where: 8 sitesUnited States
Study dates: 1 Aug 2011to 20 Jan 2019
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

ELIGIBILITY CRITERIA
HER2 positive (IHC 3+ and/or FISH positive) breast cancer patients with leptomeningeal metastases by MRI or CSF (if MRI is negative).
o Review will be performed for cases not reviewed at Northwestern for confirmation, but will not preclude patients from entering the trial (pathology report is sufficient for registration).
Patients can have concomitant brain metastases as long as they do not require active treatment or have been treated.
Patients with leptomeningeal disease from ependymomas, gliomas, and medulloblastoma will be eligible for phase I
Life expectancy > 8 weeks

Show all 23Show fewer

Normal renal (creatinine < 1.5 ULN), liver (bilirubin < 1.5 x ULN, transaminases < 3.0 x ULN, except in known hepatic metastasis, wherein may be < 5 x ULN) and blood counts (WBC > 3.0, Neutrophils > 1500, platelets >100 000, Hemoglobin > 10).
LVEF > 50%
KPS > 50
Age > 18 years
Cannot be on systemic agents (chemotherapy) that have CNS penetration unless they develop leptomeningeal metastases while on these agent(s) and have controlled systemic disease. May continue on IV trastuzumab, lapatinib or hormonal agents if controlling systemic disease and developed LM while on therapy. Patients requiring systemic chemotherapy are eligible but will not be able to start treatment until after the first assessment by imaging and cytology.
Patients may need a CSF flow study at the discretion of the treating principal investigator. If a spinal block is seen by CSF flow study or MRI, it will need local RT prior to treatment. Concurrent radiation is not allowed.
Patients should be > 2 weeks from RT treatment and all effects of treatment should have resolved
No limit on prior systemic or IT therapies.
CSF sampling to document LM if not documented on MRI.
Must be willing to have an Ommaya reservoir placed.
NO history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix) unless in complete remission and off all therapy for the disease for a minimum of 3 years.
Significant medical or psychiatric illness that would interfere with compliance and ability to tolerate treatment as outlined in the protocol.
Women of childbearing potential and sexually active males must commit to the use of effective contraception while on study.
Women may not be pregnant or breast-feeding.
Ability to sign an informed consent; can be signed by family member or health care proxy. Informed consent must be done prior to registration on study.
All patients must have given signed, informed consent prior to registration on study.
No known hypersensitivity to trial medications Note: The eligibility criteria listed above are interpreted literally and cannot be waived.

Who cannot join

Any deviations from the inclusion criteria

Trial locations and contacts

8 sites in 1 country.

City, postcode or hospital

8 sites in 1 country

United States8 sites

Texas Oncology-Austin
Austin, Texas, 78705
Tufts Medical Center
Boston, Massachusetts, 02111
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Northwestern University
Chicago, Illinois, 60611
Columbia University
New York, New York, 10032
Memorial Sloan-Kettering Cancer Center
New York, New York, 10065
Rhode Island Hospital
Providence, Rhode Island, 02903
University of California San Francisco (UCSF)
San Francisco, California, 94143-1710

Other trials in United States

About this study

Official title: Phase I/II Dose Escalation Trial to Assess Safety of Intrathecal Trastuzumab for the Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer

Phase I/II Dose Escalation Trial to Assess Safety of Intrathecal Trastuzumab for the Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer The purpose of this research study is to determine a safe dose of the drug Trastuzumab and then determine how effective this treatment is.

Read the detailed description

Phase I: Patients will be treated in cohorts of 3-6 based on standard phase I dose escalation parameters requiring 0/3 or 1/6 patients per cohort to have a DLT before dose escalation. Dosing is as follows: Cohort 1-10 mg IT, cohort 2-20 mg IT, cohort 3-30 mg IT and cohort 4-40 mg IT. Patients will be treated twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks. Toxicity for DLT will be assessed during first 4 weeks of treatment. Phase II: Patients will be treated with the MTD or maximal defined dose. Patients will be treated twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks.

Conditions: Breast Cancer
Being tested: Trastuzumab
Keywords: Breast Cancer
Medical subject headings: Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

TrastuzumabRadiation
Also called (also known as Herceptin, which, is a medicine that is used to slow or stop the growth of a cancerous tumor)
Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks

Study groups in NCT01325207
Study group	Role	What they receive
intravenous trastuzumab infusions	Experimental	A Phase I single dose study (H0407g) of intravenous trastuzumab infusions ranging from 10-500 mg resulted in dose-dependent pharmacokinetics (PK) with serum clearance of trastuzumab decreasing with an increasing dose at doses <250 mg. PK modeling of trastuzumab concentration-time data from 7 patients that were administered doses of 250 mg and 500 mg had in a mean halflife of 5.8 days (range 1-32 days). Receives: Radiation: Trastuzumab

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.
Patients will be treated using a standard 3+3 dose-escalation design for cohorts 1 and 2. This will be followed by an accelerated phase I for cohorts 3 and 4, and then a standard 3 + 3 for the 5th cohort. In the accelerated phase (cohorts 3 and 4), 1 patient will be enrolled per cohort; if a toxicity is seen in that patient then the cohort would be expanded to 6 patients to allow for 1/6 patients per cohort to have a dose limiting toxicity (DLT) before dose escalation. Cohort 5 will enroll a total of 6 patients regardless of the toxicity experienced in patient one. However, if 2 or more DLTs are observed in cohort 5, cohort 4 will be reopened to enroll of a total of 6 patients. Whatever dose is ultimately declared the MTD should have 6 patients total. If 1/6 DLTs are seen in cohort 5 that will be considered the MTD.
Dosing is as follows:
Cohort 1-10 mg IT Cohort 2-20 mg IT Cohort 3-40 mg IT Cohort 4-60 mg IT Cohort 5-80 mg IT
Measured: From treatment initiation through the first 4 weeks of treatment.
Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.
Best response will be assessed using a combination CSF cytology assessment, radiographic assessment and clinical function assessments. Best response will be defined as the best response seen during treatment as compared to baseline that is confirmed on subsequent response assessment.
Measured: Baseline then at 4 weeks, 8 weeks and then every 8 weeks +/- 3 days, until disease progression or toxicity,range of cycles completed 1-22 cycles where 1 cycle = 28 days.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Aug 201120 Jan 2019

First posted29 Mar 2011 (estimated)
Study start1 Aug 2011
Primary completion20 Jun 2016
Study completion20 Jan 2019

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Breast CancerStudies of the same condition, open and under way.
More trials run by Northwestern UniversityThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Intervention model: Sequential
Masking: None (open label)
Enrolment: 34 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01325207
Sponsor's protocol ID: NU 10C03
Other IDs: STU00040150
Status last verified: Sep 2019
First submitted: 7 Mar 2011
Last updated: 26 Sep 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

Malani R, Fleisher M, Kumthekar P, Lin X, Omuro A, Groves MD, Lin NU, Melisko M, Lassman AB, Jeyapalan S, Seidman A, Skakodub A, Boire A, DeAngelis LM, Rosenblum M, Raizer J, Pentsova E. Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer. J Neurooncol. 2020 Jul;148(3):599-606. doi: 10.1007/s11060-020-03555-z. Epub 2020 Jun 6.
PubMed 32506369

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 26 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Phase I/II Dose Escalation Trial to Assess Safety of Intrathecal Trastuzumab for the Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer
ClinicalTrials.gov ID: NCT01325207
Acronym / sponsor ID: NU 10C03
Conditions: Breast Cancer
Keywords: Breast Cancer
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 34 participants (actual)
Lead sponsor: Northwestern UniversityUniversity, hospital or other
Study start: 1 Aug 2011
Primary completion: 20 Jun 2016 (actual)
Study completion: 20 Jan 2019 (actual)
First posted: 29 Mar 2011 (estimated)
Results: Posted 28 May 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Intervention model: Sequential
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
intravenous trastuzumab infusions	Experimental	Radiation: TrastuzumabA Phase I single dose study (H0407g) of intravenous trastuzumab infusions ranging from 10-500 mg resulted in dose-dependent pharmacokinetics (PK) with serum clearance of trastuzumab decreasing with an increasing dose at doses <250 mg. PK modeling of trastuzumab concentration-time data from 7 patients that were administered doses of 250 mg and 500 mg had in a mean halflife of 5.8 days (range 1-32 days).

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (23 listed)

ELIGIBILITY CRITERIA
HER2 positive (IHC 3+ and/or FISH positive) breast cancer patients with leptomeningeal metastases by MRI or CSF (if MRI is negative).
o Review will be performed for cases not reviewed at Northwestern for confirmation, but will not preclude patients from entering the trial (pathology report is sufficient for registration).
Patients can have concomitant brain metastases as long as they do not require active treatment or have been treated.
Patients with leptomeningeal disease from ependymomas, gliomas, and medulloblastoma will be eligible for phase I

Key exclusion criteria (1 listed)

Any deviations from the inclusion criteria

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TrastuzumabAlso: (also known as Herceptin, which, is a medicine that is used to slow or stop the growth of a cancerous tumor)Trastuzumab will be administered twice per week for 4 weeks, then once per week for 4 weeks, and then every 2 weeks	Radiation	intravenous trastuzumab infusions

Primary outcome

Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.
Time frame: From treatment initiation through the first 4 weeks of treatment.
Patients will be treated using a standard 3+3 dose-escalation design for cohorts 1 and 2. This will be followed by an accelerated phase I for cohorts 3 and 4, and then a standard 3 + 3 for the 5th cohort. In the accelerated phase (cohorts 3 and 4), 1 patient will be enrolled per cohort; if a toxicity is seen in that patient then the cohort would be expanded to 6 patients to allow for 1/6 patients per cohort to have a dose limiting toxicity (DLT) before dose escalation. Cohort 5 will enroll a total of 6 patients regardless of the toxicity experienced in patient one. However, if 2 or more DLTs are observed in cohort 5, cohort 4 will be reopened to enroll of a total of 6 patients. Whatever dose is ultimately declared the MTD should have 6 patients total. If 1/6 DLTs are seen in cohort 5 that will be considered the MTD. Dosing is as follows: Cohort 1-10 mg IT Cohort 2-20 mg IT Cohort 3-40 mg IT Cohort 4-60 mg IT Cohort 5-80 mg IT
Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.
Time frame: Baseline then at 4 weeks, 8 weeks and then every 8 weeks +/- 3 days, until disease progression or toxicity,range of cycles completed 1-22 cycles where 1 cycle = 28 days.
Best response will be assessed using a combination CSF cytology assessment, radiographic assessment and clinical function assessments. Best response will be defined as the best response seen during treatment as compared to baseline that is confirmed on subsequent response assessment.

Results and safety

Results posted to the registry on 28 May 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Cohort 1 - Trastuzumab 10mg IT 2/Week	3	3
Cohort 2 - Trastuzumab 20mg IT 2/Week	3	3
Cohort 3- Trastuzumab 40mg IT 2/Week	1	1
Cohort 4 - Trastuzumab 60mg IT 2/Week	1	1
Cohort 5 - 80mg IT 2/Week	7	5
Phase II - Transtuzumab 80mg IT 2/Week	19	19

Primary outcome: Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.

Time frame: From treatment initiation through the first 4 weeks of treatment.. Number. Unit: DLTs

Measure	Cohort 1 - Trastuzumab 10mg IT 2/Week n = 3	Cohort 2 - Trastuzumab 20mg IT 2/Week n = 3	Cohort 3- Trastuzumab 40mg IT 2/Week n = 1	Cohort 4 - Trastuzumab 60mg IT 2/Week n = 1	Cohort 5 - 80mg IT 2/Week n = 7
Value	0	0	0	0	1

Primary outcome: Best Response to IT Trastuzumab: Radiological, Cytological and Clinical in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer.

Time frame: Baseline then at 4 weeks, 8 weeks and then every 8 weeks +/- 3 days, until disease progression or toxicity,range of cycles completed 1-22 cycles where 1 cycle = 28 days.. Count of participants. Unit: Participants

Measure	Treatment With Trastuzumab n = 34	Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg n = 26
Complete Response	0	0
Partial Response	6	5
Stable Disease	18	13
Progressive Disease	10	8

Population analysed: All patients were assessed for response. Patients unable to be assessed were determined to have progressive disease and counted. Cohort results for this outcome measure were analysed combined and at the MTD of 80mg IT (Cohort 5 + phase II). The objective was to determine preliminary response data for this treatment combination.

Adverse events

Time frame: Adverse events were collected over a 6 year period for the study. Patients were followed from first day of treatment until 30 days post first treatment for a maximum of 22 cycles (longest time any patient received treatment) where 1 cycle = 28 days.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Cohort 1 - Trastuzumab 10mg IT 2/Week	1 of 3 (33.3%)	3 of 3 (100%)	3 of 3
Cohort 2 - Trastuzumab 20mg IT 2/Week	2 of 3 (66.7%)	3 of 3 (100%)	3 of 3
Cohort 3- Trastuzumab 40mg IT 2/Week	1 of 1 (100%)	1 of 1 (100%)	1 of 1
Cohort 4 - Trastuzumab 60mg IT 2/Week	1 of 1 (100%)	1 of 1 (100%)	1 of 1
Cohort 5 - 80mg IT 2/Week	3 of 7 (42.9%)	7 of 7 (100%)	5 of 7
Phase II - Transtuzumab 80mg IT 2/Week	13 of 19 (68.4%)	19 of 19 (100%)	17 of 19

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 26 Sep 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 32506369Malani R, Fleisher M, Kumthekar P, Lin X, Omuro A, Groves MD, Lin NU, Melisko M, Lassman AB, Jeyapalan S, Seidman A, Skakodub A, Boire A, DeAngelis LM, Rosenblum M, Raizer J, Pentsova E. Cerebrospinal fluid circulating tumor cells as a quantifiable measurement of leptomeningeal metastases in patients with HER2 positive cancer. J Neurooncol. 2020 Jul;148(3):599-606. doi: 10.1007/s11060-020-03555-z. Epub 2020 Jun 6.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Jeffrey Raizer, MD principal investigator

Northwestern University

8 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Trastuzumab in people with Breast Cancer, run by Northwestern University at 8 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Dose Limiting Toxicities (DLT) of IT Trastuzumab in Sequential Cohorts of Escalating Doses for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. (time frame: From treatment initiation through the first 4 weeks of treatment.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01325207, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Sep 2019.