ABCSG 32: A Phase II Study of Neoadjuvant Trastuzumab+Docetaxel+NPLD+/-Bevacizumab in Her2-pos. Early Breast Cancer

Sponsor

Austrian Breast & Colorectal Cancer Study Group (Other)

Overall Status

Completed

CT.gov ID

NCT01367028

Collaborator

Hoffmann-La Roche (Industry), Cephalon (Industry)

100

Enrollment

Locations

Arms

Duration (Months)

9.1

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Multicenter randomised phase II study of neoadjuvant therapy in HER2 positive early breast cancer. Primary aim is to evaluate the cardiac toxicity of the combined treatment (trastuzumab, docetaxel, bevacizumab, NPLD) in comparison to the standard therapy.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Trastuzumab, Docetaxel Drug: Trastuzumab, Docetaxel, Bevacizumab Drug: Trastuzumab+Docetaxel+NPLD Drug: Trastuzumab+Docetaxel+NPLD+Bevacizumab	Phase 2

Detailed Description

The target study population consists of male and female pre- and postmenopausal patients with HER2-positive, adenocarcinoma of the breast (except inflammatory breast cancer, T4d) scheduled to receive neoadjuvant cytotoxic treatment.

Patients must have pathologically confirmed breast cancer with histologically confirmed HER2 over-expression. At screening, patients must have an adequate left ventricular ejection fraction (LVEF); an ECOG performance status of 0 or 1; adequate liver, renal and bone marrow function; and be free of other serious diseases that could affect protocol compliance or interpretation of results.

Patients should not be at increased risk of GI perforation, hypertension, proteinuria, wound healing complications, thromboembolism or hemorrhage. Patients must not have had another primary malignancy that could affect compliance with the protocol or interpretation of results. Patients with central nervous system (CNS) metastases are excluded. Pregnant or lactating females are excluded. Patients with hypertension (>150 mmHG systolic or >100 mmHG diastolic) and patients with a history of GI perforation, abdominal fistula or intra-abdominal abscess within 6 months of study entry are excluded.

Full anticoagulation therapy at study entry is allowed as long as the patient has been on a stable level of anticoagulants for at least 2 weeks at the time of study treatment start.

Study Design

Study Type:

Interventional

Actual Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Multicentre Randomized Phase II Study of Neoadjuvant Trastuzumab Plus Docetaxel With and Without Bevacizumab and Trastuzumab Plus Docetaxel Plus Non-pegylated Liposome-encapsulated Doxorubicin (NPLD) With and Without Bevacizumab in HER2-positive Early Breast Cancer

Study Start Date :

Jun 1, 2011

Actual Primary Completion Date :

Apr 1, 2014

Actual Study Completion Date :

Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Other: A: Trastuzumab+Docetaxel	Drug: Trastuzumab, Docetaxel 6 cycles - Day1 (Day22 = Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 100 mg/m2 by 60 min i.v. infusion Other Names: Therapy Arm A
Experimental: B: Trastuzumab+Docetaxel+Bevacizumab	Drug: Trastuzumab, Docetaxel, Bevacizumab 6 cycles - Day1 (Day22 = Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 100 mg/m2 by 60 min i.v. infusion Bevacizumab 15 mg/kg Other Names: Therapy Arm B
Experimental: C: Trastuzumab+Docetaxel+NPLD	Drug: Trastuzumab+Docetaxel+NPLD 6 cycles - Day1 (Day22=Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 75 mg/m2 by 60 min IV infusion NPLD 50 mg/m2 by 60 min i.v. infusion Other Names: Therapy Arm C
Experimental: D: Trastuzumab+Docetaxel+NPLD+Bevacizumab	Drug: Trastuzumab+Docetaxel+NPLD+Bevacizumab 6 cycles - Day1 (Day22= Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 75 mg/m2 by 60 min i.v. infusion NPLD: 50 mg/m2 by 60 min i.v. infusion; Bevacizumab 15 mg/kg Other Names: Therapy Arm D

Outcome Measures

Primary Outcome Measures

Cardiac toxicity [between day 1 of cycle 1 and day 28 after the day of final surgery]
to evaluate the cardiac toxicity of the combination trastuzumab+docetaxel+bevacizumab and trastuzumab+docetaxel+NPLD +/- bevacizumab in comparison to the standard therapy, trastuzumab+docetaxel using a composite endpoint appearing between day 1 of cycle 1 and day 28 after the day of final surgery.

Secondary Outcome Measures

Pathological complete response (ypCR) [up to 22 weeks]
ypCR defined as absence of invasive tumor at time of final surgery
Total pathological complete response (ytpCR) [up to 22 weeks]
ytpCR defined as absence of invasive tumor and tumor cells in the breast and the axillar lymphnodes (ypT0 or yDCIS and ypN=0)
Overall clinical response rate (cORR) [up to 22 weeks]
cORR defined as the percentage of patients with either a complete clinical response (cCR) or a partial clinical response (cPR), but no ypCR
Safety evaluation according to patients numbers of AEs, SAEs, lab test abnormalities, cardiac assessment, clinical evaluation [up to 22 weeks]
Safety (AEs, SAEs, lab test abnormalities, cardiac assessment, clinical evaluation)of the combination trastuzumab and docetaxel with bevacizumab and trastuzumab, docetaxel, and NPLD plus/minus bevacizumab at the time of final surgery

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Female or male, age ≥ 18 years
Pathologically confirmed invasive primary breast adenocarcinoma (except inflammatory breast cancer, T4d) scheduled for taxane containing neoadjuvant systemic treatment with/without palpable lymph nodes.
Documented HER2 protein overexpression as determined by immunohistochemistry (IHC) 3+ or by demonstrated HER2/c-erbB2 gene amplification of the primary tumor by a local laboratory.
LVEF ≥ 55% measured by echocardiography or MUGA within 4 weeks before randomization
ECOG Performance Status ≤ 1
Able and willing to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Written Informed Consent

Exclusion Criteria:

Current Treatment

Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine.
Chronic daily treatment with corticosteroids excl. inhaled steroids.
Chronic daily treatment with aspirin and aspirin analogs or clopidogrel
Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization or anticipation of need for major surgery during the course of study treatment
Current or recent (within 30 days prior to randomization) treatment with another investigational drug or participation in another investigational study.

Laboratory

Inadequate bone marrow function
Inadequate liver function
Inadequate renal function
Patients not receiving anticoagulant medication who have activated partial thromboplastin time (aPTT) within 7 days prior to Day1 of the cycle 1.

Concomitant Conditions

Other malignancy within the last 5 years before randomization except for curatively treated carcinoma in situ of the cervix or non-melanomatous skin cancer
Evidence of distant metastasis judged clinically and at least by chest-X-ray, liver-sonography and bone scan. If there is any clinical suspicion of brain metastasis, a CT-scan or MRI of the brain must be conducted within 4 weeks prior to randomization.
Serious concurrent disease which could affect compliance with the protocol or interpretation of results, including, but not limited to:
Active infection requiring i.v. antibiotics
Uncontrolled hypertension
Clinically significant history of cardiovascular disease as indicated by: cerebrovascular accident or stroke; myocardial infarction; unstable angina; NYHA Grade II or greater CHF; cardiac arrhythmia requiring medication; clinically significant valvular heart disease.
Dyspnea at rest necessitating supportive oxygen therapy or with significant pleural effusions
Poorly controlled diabetes mellitus
History or evidence upon physical/neurological examination of CNS disease unrelated to cancer (e.g. uncontrolled seizures) unless adequately treated with standard medical therapy
History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding
History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months of randomization
Serious non-healing wound, peptic ulcer, or bone fracture
Clinically significant malabsorption syndrome, ulcerative colitis, disease affecting GI function, resection of the stomach or small bowel, or inability to take oral medication
Uncorrected hypokalemia or hypomagnesemia
Organ allografts requiring immunosuppressive therapy
Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect patient compliance with study routines, or place the patient at high risk from treatment related complications.
Known hypersensitivity to any of the study drugs/excipients.
Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.

Other

Pregnant, lactating females or women of childbearing potential without a negative pregnancy test
Fertile males or females of childbearing potential
Patients not accessible for treatment or follow-up

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University of Graz-Oncology; Coop. Group	Graz	Styria	Austria	8036
2	State Hospital Leoben	Leoben	Styria	Austria	8700
3	Gynaegological Medical University Innsbruck	Innsbruck	Tyrol	Austria	6020
4	District Hospital Kufstein	Kufstein	Tyrol	Austria	6330
5	Hospital BHS Linz, Coop. Study Group	Linz	Upper Austria	Austria	4010
6	AKH Linz	Linz	Upper Austria	Austria	4020
7	State Hospital Feldkirch, Coop. Group	Feldkirch	Vorarlberg	Austria	6807
8	Paracelsus Medical University Salzburg-Oncology, Coop. Group	Salzburg		Austria	5020
9	Med. Univ. Vienna; General Hospital Vienna	Vienna		Austria	1090
10	Medical University Vienna, General Hospital	Vienna		Austria	1090
11	State Hospital Vienna-Hietzing	Vienna		Austria	1130