Dual Blockage With Afatinib and Trastuzumab as Neoadjuvant Treatment for Patients With Locally Advanced or Operable Breast Cancer Receiving Taxane-anthracycline Containing Chemotherapy

NCT01594177 | Completed Phase 2 DMC

• 2 other identifiers: GBG 702011-004704-38
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 1

Brief Summary

Anthracycline/taxane based combination chemotherapy of at least 18 weeks represents the standard of care in the neoadjuvant setting. In HER2 positive disease trastuzumab is given simultaneously. Neoadjuvant anthracycline-taxane-based chemotherapy given simul-taneously with trastuzumab achieves a pCR rate of approx. 40%. Recent data showed that a double blockade of the HER2 receptor (e.g. trastuzumab + lapatinib; trastuzumab + pertuzumab) given together with a few cycles of chemotherapy can increase the pCR rate by approximately 20%. So far, there is uncertainty, if afatinib (BIBW 2992), an irreversible HER family blocker can lead to an even more complete blockade of the HER2 pathway when given in combination with trastuzumab. The neoadjuvant setting provides the unique opportunity to assess precisely and at short term the effect of systemic treatment by assessing the pCR at surgery. It also allows treating patients with HER2 positive breast cancer before surgery without standard trastuzumab treatment, as, according to current guideline, trastuzumab can also be given sequentially after surgery. The aim of the study is to show that chemotherapy + trastuzumab + afatinib can achieve significant pCR rates.

Conditions

Unilateral HER2 Positive Breast Cancer

Keywords

DAFNE; GBG 70; GBG; German Breast Group; GBG Forschungs GmbH; Afatinib; neo-adjuvant; HER-2 positive breast cancer; BIBW 2992; 1200.159

Outcome Measures

Primary Outcomes (1)

• Pathological Complete Response

  To compare the pathological complete response (pCR = ypT0/is ypN0) rates of neoadjuvant treatment of afatinib in combination with weekly paclitaxel + trastuzumab followed by epirubicin/ cyclophosphamide/ trastuzumab in patients with HER2-positive primary breast cancer.

  30 weeks

Secondary Outcomes (6)

• Pathological Complete Response

  30 weeks

• Response Rate by Physical Examination and Imaging Tests

  30 weeks

• Conservation Rate

  30 weeks

• Number of Participants with (Serious) Adverse Events as a Measure of Safety and Tolerability

  30 weeks

• Number of Participants with Skin Toxicity and Diarrhea as (Serious) Adverse Events as a Measure of Safety and Tolerability and Pathological Complete Response

  30 weeks

Study Arms (1)

Treatment arm

EXPERIMENTAL

Afatinib-Trastuzumab (6 weeks) followed by Afatinib\*-Paclitaxel-Trastuzumab (12 weeks) followed by Epirubicin-Cyclophosphamide-Trastuzumab (12 weeks). \*only 11 weeks.

Drug: Afatinib; Drug: Trastuzumab; Drug: Paclitaxel; Drug: Epirubicin; Drug: Cyclophosphamide

Interventions

Afatinib DRUG

20 mg daily for 17 weeks (first two weeks every second day).

Treatment arm

Trastuzumab DRUG

First cycle: loading dose 8 mg/kg (day 1 q day 22), thereafter maintenance dose for 9 cycles: 6 mg/kg (day 1 q day 22).

Also known as: HERCEPTIN

Treatment arm

Paclitaxel DRUG

80 mg/m² i.v. given weekly on day 1 q day 8 for 12 weeks.

Treatment arm

Epirubicin DRUG

90 mg/m² i.v. given on day 1 q day 22 for 4 cycles.

Treatment arm

Cyclophosphamide DRUG

600 mg/m² i.v. given on day 1 q day 22 for 4 cycles.

Treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent for all study procedures according to local regulatory requirements prior to beginning of specific protocol procedures.
• Complete baseline documentation must be sent to GBG Forschungs GmbH.
• Unilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not allowed. Tumor lesion in the breast with a sonographical size of ≥ 2 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
• Operable or locally advanced or inflammatory breast cancer (cT2 - cT4a-d). In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
• Centrally confirmed positive HER2 status detected on core biopsy. HER2-positive is defined as IHC 3+ by a validated test method or FISH/SISH ratio \> 2.0. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the Department of Pathology at the Charité, Berlin, prior to regsitration.
• Centrally confirmed hormone receptor status (ER/PgR).
• Age ≥ 18 years.
• Karnofsky Performance status ≥ 80%.
• Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to registration. Results must be above 55%.
• Laboratory requirements:
• Hematology
• Absolute neutrophil count (ANC) ≥ 2.0 x 109/L and
• Platelets ≥ 100 x 109/L and
• Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L) Hepatic function
• Total bilirubin ≤ 1.5x UNL and

You may not qualify if:

• Bilateral breast cancer.
• Prior chemotherapy for any malignancy.
• Prior radiation therapy for breast cancer.
• Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilisation) during study treatment.
• Inadequate general condition (not fit for anthracycline-taxane based chemotherapy) as per investigator´s assessment.
• Previous malignant disease with a disease-free period of less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
• Known or pre-existing interstitial lung disease.
• Known or suspected congestive heart failure (NYHA \> I) or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP \> 160/90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
• History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
• Chronic-inflammatory bowel diseases.
• Pre-existing motor or sensory neuropathy of a severity grade ≥ 2 by NCI-CTCAE criteria.
• No evidence or history of infection (including hepatitis B, C or HIV).
• Known hypersensitivity reaction to one of the investigational compounds or incorporated substances used in this protocol.
• Definite contraindications for the use of corticosteroids except inhalative corticoids.
• Concurrent treatment with:

Sponsors & Collaborators

• GBG Forschungs GmbH: lead
• Boehringer Ingelheim: collaborator

Study Sites (1)

Rotkreuzklinikum München

München, 80634, Germany

Location

MeSH Terms

Interventions

Afatinib; Trastuzumab; Paclitaxel; Epirubicin; Cyclophosphamide

Intervention Hierarchy (Ancestors)

Amides; Organic Chemicals; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes; Doxorubicin; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Study Officials

• Claus A Hanusch, MD, PhD

  Rotkreuzklinikum München, 80634 München, Rotkreuzplatz 8

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 3, 2012
• First Posted: May 8, 2012
• Study Start: May 1, 2012
• Primary Completion: March 1, 2014
• Study Completion: March 1, 2014
• Last Updated: March 13, 2014

Record last verified: 2014-03

Locations

DE (1)