NCT01325207

Intrathecal Trastuzumab for Leptomeningeal Metastases in HER2+ Breast Cancer

Completed Phase 1, PHASE2 Results posted Last updated 26 September 2019

What this trial tests

Phase 1, PHASE2 trial testing Trastuzumab in Breast Cancer in 34 participants. Completed in 20 January 2019.

Timeline

1 August 2011

Primary endpoint
20 June 2016

20 January 2019

Quick facts

Lead sponsor	Northwestern University
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	34
Start date	1 August 2011
Primary completion	20 June 2016
Estimated completion	20 January 2019
Sites	8 locations across United States

Drugs / interventions tested

• Trastuzumab (trastuzumab) — full drug profile →

Conditions studied

• Breast Cancer — all drugs for Breast Cancer →

Sponsor

Northwestern University

Who can join

18 and older, any sex, with Breast Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

Group	Value	95% CI
Cohort 1 - Trastuzumab 10mg IT 2/Week	0
Cohort 2 - Trastuzumab 20mg IT 2/Week	0
Cohort 3- Trastuzumab 40mg IT 2/Week	0
Cohort 4 - Trastuzumab 60mg IT 2/Week	0
Cohort 5 - 80mg IT 2/Week	1

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

Group	Value	95% CI
Treatment With Trastuzumab	0
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	0
Treatment With Trastuzumab	6
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	5
Treatment With Trastuzumab	18
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	13
Treatment With Trastuzumab	10
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	8

Progression Free Survival (PRS) at 6 Months and at 12 Months in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. Secondary · At 6 and 12 months from start of treatment

Progression Free Survival (PFS) will be measured from the time of treatment initiation until the first documentation of progression. To estimate the probability of PFS at 6 months and 12 months, Kaplan-Meier curves will be calculated and PFS at 6 months and 12 months will be determined from the progression-free survival curve. Progression will be defined as worsening clinical signs or development of new clinical symptoms that the Investigator feels can be attributed to Leptomeningeal disease.

PFS at 6 months

Group	Value	95% CI
Treatment With Trastuzumab	0.235
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	0.269

PFS at 12 months

Group	Value	95% CI
Treatment With Trastuzumab	0.118
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	0.115

Overall Survival (OS) at 6 and 12 Months in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. Secondary · At 6 and 12 months from start of treatment

Overall Survival (OS) will be measured from the time of treatment initiation until death from any cause. To estimate OS probability at 6 and 12 months, Kaplan-Meier curves will be calculated and OS at 612 months will be determined from the overall survival curve.

OS at 6 months

Group	Value	95% CI
Treatment With Trastuzumab	0.562
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	0.542

OS at 12 months

Group	Value	95% CI
Treatment With Trastuzumab	0.406
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	0.458

Median Progression Free Survival (PFS) in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. Secondary · From start of treatment, and during treatment until progressive disease for up to 30 months.

Progression Free Survival (PFS) will be measured from the time of treatment initiation until the first documentation of progression. To estimate PFS, Kaplan-Meier curves will be calculated and the median PFS will be determined from the progression-free survival curve. Progression will be defined as worsening clinical signs or development of new clinical symptoms that the Investigator feels can be attributed to Leptomeningeal disease.

Group	Value	95% CI
Treatment With Trastuzumab	1.885	1.541 – 3.738
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	2.148	1.016 – 7.344

Median Overall Survival (OS) in Treatment With Intrathecal Trastuzumab for Patients With Leptomeningeal Metastases in HER2+ Breast Cancer. Secondary · From start of treatment until death from any cause for up to 60 months.

Overall Survival (OS) will be measured from start of treatment until death from any cause. To estimate OS, Kaplan-Meier curves will be calculated and median OS will be determined from the progression-free survival curve.

Group	Value	95% CI
Treatment With Trastuzumab	8.738	5.607 – 17.311
Cohort 5 + Phase II - Intrathecal Trastuzumab- 80 mg	8.328	5.148 – 19.541

Adverse events — posted to ClinicalTrials.gov

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.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort 1 - Trastuzumab 10mg IT 2/Week

Serious: 1/3 (33%)

Deaths: 3/3

Cohort 2 - Trastuzumab 20mg IT 2/Week

Serious: 2/3 (67%)

Deaths: 3/3

Cohort 3- Trastuzumab 40mg IT 2/Week

Serious: 1/1 (100%)

Deaths: 1/1

Cohort 4 - Trastuzumab 60mg IT 2/Week

Serious: 1/1 (100%)

Deaths: 1/1

Cohort 5 - 80mg IT 2/Week

Serious: 3/7 (43%)

Deaths: 5/7

Phase II - Transtuzumab 80mg IT 2/Week

Serious: 13/19 (68%)

Deaths: 17/19

Serious adverse events (28 terms)

Reaction	System	Cohort 1 - Trastuzumab 10m…	Cohort 2 - Trastuzumab 20m…	Cohort 3- Trastuzumab 40mg…	Cohort 4 - Trastuzumab 60m…	Cohort 5 - 80mg IT 2/Week	Phase II - Transtuzumab 80…
Seizure	Nervous system disorders	—	—	—	—	—	—
Chemical meningitis	Infections and infestations	—	—	—	—	—	—
Worsening neurological symptoms	Nervous system disorders	—	—	—	—	—	—
Pericardial effusion	Cardiac disorders	—	—	—	—	—	—
Dysphasia	Nervous system disorders	—	—	—	—	—	—
Worsening Mental Status	Nervous system disorders	—	—	—	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—	—	—	—
Abdominal muscle wall hemorrhage	Gastrointestinal disorders	—	—	—	—	—	—
Syncope	Nervous system disorders	—	—	—	—	—	—
Death due to aspiration pneumonia	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Dehydration	Gastrointestinal disorders	—	—	—	—	—	—
Gastroenteritis	Gastrointestinal disorders	—	—	—	—	—	—
Dehydration	Gastrointestinal disorders	—	—	—	—	—	—
Esophagitis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Vasivagal reaction	Nervous system disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Colonic perforation	Gastrointestinal disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Thromboembolic event (DVT)	Vascular disorders	—	—	—	—	—	—
Death due to progressive disease	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—
Pain in back and extremities	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Lung infection	Infections and infestations	—	—	—	—	—	—
Clinical deterioration	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—
Wound infection	Infections and infestations	—	—	—	—	—	—
Enterocolitis infectious	Infections and infestations	—	—	—	—	—	—

Other adverse events (99 terms — click to expand)

Reaction	System	Cohort 1 - Trastuzumab 10m…	Cohort 2 - Trastuzumab 20m…	Cohort 3- Trastuzumab 40mg…	Cohort 4 - Trastuzumab 60m…	Cohort 5 - 80mg IT 2/Week	Phase II - Transtuzumab 80…
Anemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Lymphocyte Count Decreased	Investigations	—	—	—	—	—	—
Hypoalbuminemia	Metabolism and nutrition disorders	—	—	—	—	—	—
White Blood Cell Decreased	Investigations	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—
Alanine Aminotransferase Increased	Investigations	—	—	—	—	—	—
Platelet Count Decreased	Investigations	—	—	—	—	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Alkaline Phosphatase Increased	Investigations	—	—	—	—	—	—
Aspartate Aminotransferase Increased	Investigations	—	—	—	—	—	—
Hypocalcemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Headaches	Nervous system disorders	—	—	—	—	—	—
Seizure	Nervous system disorders	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Diarrhea	Gastrointestinal disorders	—	—	—	—	—	—
Hemorrhoids	Gastrointestinal disorders	—	—	—	—	—	—
Gait disturbance	General disorders	—	—	—	—	—	—
Pain	General disorders	—	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—
Dehydration	Metabolism and nutrition disorders	—	—	—	—	—	—
Hypomagnesemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Muscle Weakness Lower Limb	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—
Meningismus	Nervous system disorders	—	—	—	—	—	—
Urinary incontinence	Renal and urinary disorders	—	—	—	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—	—	—	—
Thromboembolic Event	Vascular disorders	—	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Palpitations	Cardiac disorders	—	—	—	—	—	—
Hearing impaired	Ear and labyrinth disorders	—	—	—	—	—	—
Tinnitus	Ear and labyrinth disorders	—	—	—	—	—	—
Blurred vision	Eye disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Dry mouth	Gastrointestinal disorders	—	—	—	—	—	—
Dysphagia	Gastrointestinal disorders	—	—	—	—	—	—

Most-reported serious reactions: Seizure, Chemical meningitis, Worsening neurological symptoms, Pericardial effusion, Dysphasia, Worsening Mental Status, Hyponatremia, Abdominal muscle wall hemorrhage.

Data from ClinicalTrials.gov NCT01325207 adverse events section.

Sponsor's own description

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. This study will investigate the safety and effects of this drug when given directly into the spinal fluid.

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors.
   Le Rhun E, Taillibert S, Chamberlain MC. · · 2013 · cited 223× · PMID 23717798 · DOI 10.4103/2152-7806.111304
2. Treatment strategies for breast cancer brain metastases.
   Bailleux C, Eberst L, Bachelot T. · · 2021 · cited 170× · PMID 33250512 · DOI 10.1038/s41416-020-01175-y
3. Leptomeningeal metastasis from systemic cancer: Review and update on management.
   Wang N, Bertalan MS, Brastianos PK. · · 2018 · cited 167× · PMID 29165794 · DOI 10.1002/cncr.30911
4. CNS metastases in breast cancer: old challenge, new frontiers.
   Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, et al · · 2013 · cited 163× · PMID 24298071 · DOI 10.1158/1078-0432.ccr-13-0790
5. Leptomeningeal disease: current diagnostic and therapeutic strategies.
   Nayar G, Ejikeme T, Chongsathidkiet P, Elsamadicy AA, et al · · 2017 · cited 155× · PMID 29069871 · DOI 10.18632/oncotarget.20272
6. Characteristics and Outcomes of Patients With Breast Cancer With Leptomeningeal Metastasis.
   Morikawa A, Jordan L, Rozner R, Patil S, et al · · 2017 · cited 95× · PMID 27569275 · DOI 10.1016/j.clbc.2016.07.002
7. Leptomeningeal metastasis from solid tumours: EANO-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.
   Le Rhun E, Weller M, van den Bent M, Brandsma D, et al · · 2023 · cited 93× · PMID 37863528 · DOI 10.1016/j.esmoop.2023.101624
8. How we treat patients with leptomeningeal metastases.
   Le Rhun E, Preusser M, van den Bent M, Andratschke N, et al · · 2019 · cited 86× · PMID 31231573 · DOI 10.1136/esmoopen-2019-000507