Phase II Study With the Trifunctional Antibody Ertumaxomab to Treat Metastatic Breast Cancer After Progression on Trastuzumab Therapy

• Sponsor: Neovii Biotech (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00522457
• Collaborator: Fresenius Biotech North America (Industry)
• Enrollment: 19
• Locations: 5
• Duration (Months): 23
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study has the purpose to demonstrate clinical efficacy of the investigational new drug ertumaxomab in patients with human epidermal growth factor receptor-2 (HER-2/neu) overexpressing (3+ or 2+ with a positive Fluorescence In Situ Hybridization (FISH) test result) metastatic breast cancer progressing after trastuzumab treatment.

Ertumaxomab is a trifunctional bispecific antibody targeting Her-2/neu on tumor cells and CD3 on T cells. Trifunctional antibodies represent a new concept for targeted anticancer therapy. This new antibody class has the capability to redirect T cells and accessory immune effector cells (e.g. macrophages, dendritic cells [DCs] and natural killer [NK] cells) to the tumor site. According to preclinical data, trifunctional antibodies activate these immune cells, which can trigger a complex anti-tumor immune response.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer; Advanced Breast Cancer	Drug: ertumaxomab	Phase 2

Detailed Description

This study is an open-label, non-randomized, uncontrolled, two-stage phase II study evaluating the efficacy and safety of ertumaxomab. Ertumaxomab will be administered three times at 7 day intervals by constant rate 3 hour intravenous (i.v.) infusions according to the following dose schedule: 10 µg (day 0); 100 µg (day 7 ± 1 day) and 100 µg (day 14 ± 1 day) (flat doses).

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study Of The Trifunctional Bispecific Anti-HER-2/Neu x Anti-CD3 Antibody Ertumaxomab In Patients With HER-2/Neu Overexpressing (3+ Or 2+/FISH+) Metastatic Breast Cancer Progressing After Trastuzumab Treatment
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Outcome Measures

Primary Outcome Measures

1. Clinical Efficacy Measured by Objective Response Rate (Best Response During the Course of the Study) [patients are monitored for 6 months]

Secondary Outcome Measures

1. Duration of Response [patients are monitored for 6 months]

   The study was prematurely terminated, therefore no participants were analyzed

2. Clinical Benefit Rate [patients are monitored for 6 months]

   The study was prematurely terminated, therefore no participants were analyzed

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Women ≥ 18 years, Negative pregnancy test at screening and life expectancy of at least 3 months

• metastatic (stage IV) and not curable adenocarcinoma of the breast

• Measurable disease, defined as at least one lesion that is measurable in one dimension (RECIST)

• HER-2 overexpression 3+ or 2+ FISH positive

• Patients must have received one prior therapy with trastuzumab as last treatment before entry into the study. If trastuzumab was given as single agent treatment, patients must have received prior chemotherapy for metastatic disease

• Trastuzumab has been discontinued before study entry

• disease had progressed during or after trastuzumab therapy

• Eastern Cooperative Oncology Group (ECOG)performance score of ≤ 2

• Adequate hematological, liver and kidney function

Key Exclusion Criteria:

• Women who are pregnant or breast feeding

• Any history or symptoms indicative of brain or central nervous system metastases

• Prior diagnosis of any malignancy not cured by surgery alone less than 5 years before study entry (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin)

• Human anti-murine antibody positive or hypersensitivity to murine proteins and any other component of the study drug

• Known autoimmune diseases, Human immunodeficiency virus (HIV), hepatitis B or C infection as well as other acute or chronic infection or other concurrent non-malignant co-morbidities that are uncontrolled

• Any concurrent chemotherapy, hormonal therapy, immunotherapy or corticoid therapy

• Concurrent antibiotic treatment

• Any concurrent investigational treatment for metastatic disease

Cardiovascular exclusion criteria:

• Unstable or uncontrolled pectorial angina

• Myocardial infarction during the last 6 months

• Valvular heart disease that requires treatment

• Cardiomyopathy (congestive, hypertrophic or restrictive)

• Acute myocarditis

• Congestive heart failure (CHF): dyspnea, clinically or radiologically diagnosed

• Left ventricular ejection fraction (LVEF)outside institution's normal range based on echocardiography at rest

• Left ventricular diameter > 56 mm based on M-mode echocardiography at rest

• Arrhythmias that require treatment (atrioventricular block II/III degree, atrial fibrillation, ventricular tachycardia)

• Poorly or uncontrolled hypertension, asthma, seizures, allergies, pulmonary dysfunction

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Minneapolis	Minnesota	United States
2		Lebanon	New Hampshire	United States
3		New York	New York	United States
4		Ottawa	Ontario	Canada
5		Montreal	Quebec	Canada

Sponsors and Collaborators

• Neovii Biotech
• Fresenius Biotech North America

Investigators

• Principal Investigator: Gary Schwartz, MD, Dartmouth Hitchcock Medical Center/Norris Cotton Cancer Center; Lebanon, NH

Study Documents (Full-Text)

None provided.

More Information

Publications

• Kiewe P, Hasmüller S, Kahlert S, Heinrigs M, Rack B, Marmé A, Korfel A, Jäger M, Lindhofer H, Sommer H, Thiel E, Untch M. Phase I trial of the trifunctional anti-HER2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer. Clin Cancer Res. 2006 May 15;12(10):3085-91.
• Riesenberg R, Buchner A, Pohla H, Lindhofer H. Lysis of prostate carcinoma cells by trifunctional bispecific antibodies (alpha EpCAM x alpha CD3). J Histochem Cytochem. 2001 Jul;49(7):911-7.
• Ruf P, Lindhofer H. Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody. Blood. 2001 Oct 15;98(8):2526-34.
• Zeidler R, Mysliwietz J, Csánady M, Walz A, Ziegler I, Schmitt B, Wollenberg B, Lindhofer H. The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br J Cancer. 2000 Jul;83(2):261-6.
• Zeidler R, Reisbach G, Wollenberg B, Lang S, Chaubal S, Schmitt B, Lindhofer H. Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing. J Immunol. 1999 Aug 1;163(3):1246-52.

• ClinicalTrials.gov Identifier: NCT00522457
• Other Study ID Numbers: IV-ERT-BC-04
• First Posted: Aug 29, 2007
• Last Update Posted: Apr 29, 2011
• Last Verified: Apr 1, 2011

• Keywords provided by , ,: Breast Cancer; investigational drug; drug therapy; Antineoplastic Protocols; Immunotherapy; Metastatic breast cancer; Advanced breast cancer; Stage IV breast cancer; Her-2/neu expressing breast cancer; Her-2/neu; Trastuzumab refractory
• Additional relevant MeSH terms: Breast Neoplasms

Study Results

Participant Flow

Recruitment Details	Open-label phase 2 study evaluating the efficacy and safety of ertumaxomab for the treatment of metastatic breast cancer tumors. Ertumaxomab will be administered 3 times at 7 day intervals by constant rate 3 hour intravenous (IV) infusions according to the following dose schedule: 10 µg (day 0); 100 µg (day 7±1)and 100 µg(day14±1)(flat doses).
Pre-assignment Detail	Patients were required to complete screening procedures and up to five treatment visits.

Arm/Group Title	Ertumaxomab
Arm/Group Description
Period Title: Overall Study
STARTED	19
COMPLETED	1
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Ertumaxomab
Arm/Group Description
Overall Participants	19
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	19 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	19 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	12 63.2%
Canada	7 36.8%

Outcome Measures

1. Primary Outcome

Title	Clinical Efficacy Measured by Objective Response Rate (Best Response During the Course of the Study)
Time Frame	patients are monitored for 6 months

Outcome Measure Data

Analysis Population Description

The study was prematurely terminated, therefore no participants were analyzed. The primary endpoint was the objective response rate (ORR) to ertumaxomab (best response during the course of the study), defined as the number of patients with CR or PR according to RECIST, relative to the total population of treated patients

Arm/Group Title	Ertumaxomab
Arm/Group Description
Measure Participants	0

2. Secondary Outcome

Title	Duration of Response
Description	The study was prematurely terminated, therefore no participants were analyzed
Time Frame	patients are monitored for 6 months

Outcome Measure Data

Analysis Population Description

The study was prematurely terminated, therefore no participants were analyzed

Arm/Group Title	Ertumaxomab
Arm/Group Description
Measure Participants	0

3. Secondary Outcome

Title	Clinical Benefit Rate
Description	The study was prematurely terminated, therefore no participants were analyzed
Time Frame	patients are monitored for 6 months

Outcome Measure Data

Analysis Population Description

The study was prematurely terminated, therefore no participants were analyzed

Arm/Group Title	Ertumaxomab
Arm/Group Description
Measure Participants	0

Adverse Events

Arm/Group Title	Ertumaxomab
Arm/Group Description
All Cause Mortality
	Ertumaxomab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ertumaxomab
	Affected / at Risk (%)	# Events
Total	11/19 (57.9%)
Cardiac disorders
supraventricular tachycardia	1/19 (5.3%)	2
Gastrointestinal disorders
abscess intestinal	1/19 (5.3%)	1
nausea	1/19 (5.3%)	1
General disorders
pyrexia	4/19 (21.1%)	4
asthenia	1/19 (5.3%)	1
infusion related reaction	1/19 (5.3%)	2
Hepatobiliary disorders
bile duct obstruction	1/19 (5.3%)	1
liver abscess	1/19 (5.3%)	1
Infections and infestations
clostridial infection	1/19 (5.3%)	1
urinary tract infection	1/19 (5.3%)	1
Investigations
medical observation	3/19 (15.8%)	11
Metabolism and nutrition disorders
dehydration	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
pain in extremity	1/19 (5.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
malignant neoplasm progression	2/19 (10.5%)	2
Nervous system disorders
confusional state	1/19 (5.3%)	1
Psychiatric disorders
somnolence	1/19 (5.3%)	1
Renal and urinary disorders
hydronephrosis	2/19 (10.5%)	2
renal failure	1/19 (5.3%)	1
ureteric obstruction	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
pleural effusion	1/19 (5.3%)	1
respiratory acidosis	1/19 (5.3%)	1
Vascular disorders
hypotension	4/19 (21.1%)	6
hemoptysis	1/19 (5.3%)	1
Other (Not Including Serious) Adverse Events
	Ertumaxomab
	Affected / at Risk (%)	# Events
Total	19/19 (100%)
Blood and lymphatic system disorders
lymphopenia	4/19 (21.1%)	7
anaemia	3/19 (15.8%)	3
leukopenia	2/19 (10.5%)	2
neutropenia	2/19 (10.5%)	2
Cardiac disorders
tachycardia	4/19 (21.1%)	7
sinus tachycardia	2/19 (10.5%)	2
supraventricular tachycardia	1/19 (5.3%)	2
Gastrointestinal disorders
nausea	13/19 (68.4%)	21
vomiting	10/19 (52.6%)	16
abdominal pain	3/19 (15.8%)	5
constipation	3/19 (15.8%)	3
diarrhoea	3/19 (15.8%)	6
abdominal discomfort	1/19 (5.3%)	1
abdominal distension	1/19 (5.3%)	3
abscess intestinal	1/19 (5.3%)	1
oral pain	1/19 (5.3%)	1
General disorders
chills	14/19 (73.7%)	27
pyrexia	13/19 (68.4%)	28
fatigue	11/19 (57.9%)	15
pain	3/19 (15.8%)	3
chest pain	2/19 (10.5%)	3
flank pain	2/19 (10.5%)	2
flushing	2/19 (10.5%)	2
infusion related reaction	2/19 (10.5%)	3
asthenia	1/19 (5.3%)	1
lethargy	1/19 (5.3%)	1
Hepatobiliary disorders
bile duct obstruction	1/19 (5.3%)	1
jaundice	1/19 (5.3%)	1
liver abscess	1/19 (5.3%)	1
Immune system disorders
cytokine release syndrome	1/19 (5.3%)	1
Infections and infestations
oral herpes	3/19 (15.8%)	3
clostridial infection	1/19 (5.3%)	1
localised infection	1/19 (5.3%)	1
upper respiratory tract infection	1/19 (5.3%)	1
urinary tract infection	1/19 (5.3%)	1
Investigations
aspartate aminotransferase increased	4/19 (21.1%)	5
alanine aminotransferase increased	3/19 (15.8%)	4
c-reactive protein increased	3/19 (15.8%)	5
medical observation	3/19 (15.8%)	11
blood alkaline phosphatase increased	1/19 (5.3%)	1
c-reactive protein	1/19 (5.3%)	2
electrocardiogram QT prolonged	1/19 (5.3%)	1
gamma-glutamyltransferase increased	1/19 (5.3%)	1
weight decreased	1/19 (5.3%)	1
Metabolism and nutrition disorders
anorexia	5/19 (26.3%)	7
hypocalcaemia	2/19 (10.5%)	2
decreased appetite	1/19 (5.3%)	1
dehydration	1/19 (5.3%)	1
hypermagnesemia	1/19 (5.3%)	2
hypokalaemia	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
back pain	3/19 (15.8%)	3
pain in extremity	3/19 (15.8%)	3
arthralgia	2/19 (10.5%)	3
myalgia	2/19 (10.5%)	5
muscle spasms	1/19 (5.3%)	1
musculoskeletal stiffness	1/19 (5.3%)	1
pain in jaw	1/19 (5.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
malignant neoplasm progression	2/19 (10.5%)	2
tumour pain	2/19 (10.5%)	3
Nervous system disorders
headaches	14/19 (73.7%)	20
dizziness	2/19 (10.5%)	2
amnesia	1/19 (5.3%)	1
confusional state	1/19 (5.3%)	1
dysgeusia	1/19 (5.3%)	1
neuropathy	1/19 (5.3%)	1
peripheral sensory neuropathy	1/19 (5.3%)	1
photopsia	1/19 (5.3%)	1
Psychiatric disorders
anxiety	2/19 (10.5%)	2
insomnia	2/19 (10.5%)	2
mood altered	1/19 (5.3%)	1
somnolence	1/19 (5.3%)	1
Renal and urinary disorders
hydronephrosis	2/19 (10.5%)	2
renal failure	1/19 (5.3%)	1
ureteric obstruction	1/19 (5.3%)	1
Reproductive system and breast disorders
oedema genital	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
cough	4/19 (21.1%)	4
wheezing	3/19 (15.8%)	3
dyspnoea	1/19 (5.3%)	1
dyspnoea exertional	1/19 (5.3%)	1
pleural effusion	1/19 (5.3%)	1
respiratory acidosis	1/19 (5.3%)	1
dysphonia	1/19 (5.3%)	1
Skin and subcutaneous tissue disorders
erythema	2/19 (10.5%)	2
hyperhidrosis	1/19 (5.3%)	1
ingrowing nail	1/19 (5.3%)	1
pallor	1/19 (5.3%)	1
rash	1/19 (5.3%)	1
Vascular disorders
hypotension	9/19 (47.4%)	16
hpertension	4/19 (21.1%)	6
hemoptysis	1/19 (5.3%)	1
lymphoedema	1/19 (5.3%)	1

Limitations/Caveats

The study was prematurely terminated. This decision was based on strategic changes in the company's research and development program and resulted in limited patient data.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Site may publish the results of the Study after such cooperative publication, or 1 year after Sponsor's final evaluation of all the Study data from all sites, whichever occurs first. Prior to any submission for publication, presentation, or communication of results or information arising from the Study, Investigator shall provide Fresenius Biotech at least 90 days for review and comment upon the manuscript or other material for such publication or presentation.