Unilateral HER2 Positive Breast CancerPhase 2DAFNENCT01594177
Dual Blockage With Afatinib and Trastuzumab as Neoadjuvant Treatment for Patients With Locally Advanced or Operable Breast Cancer Receiving Taxane-anthracycline Containing Chemotherapy
A Phase 2 study testing Afatinib, Trastuzumab and Paclitaxel in people with Unilateral HER2 Positive Breast Cancer, run by GBG Forschungs GmbH at 1 site in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Unilateral HER2 Positive Breast Cancer
- What is being tested?
- Afatinib, Trastuzumab and Paclitaxel
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 65 participants
- Where
- 1 siteGermany
- Study dates
- May 2012to Mar 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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
- ASAT (SGOT) and ALAT (SGPT) ≤ 1.5x UNL and
- Alkaline phosphatase ≤ 2.5x UNL. Renal function
- Creatinine ≤ 175 µmol/L (2 mg/dL) < 1.5x UNL.
- Negative pregnancy test (urine or serum) within 14 days prior to registration for all women of childbearing potential.
- Complete staging work-up within 3 months prior to registration. All patients must have bilateral mammography, breast ultrasound (≤ 21 days), breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan done. In case of positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated.
- Patients must be available and compliant for treatment and follow-up. Patients registered on this trial must be treated at the participating or at a cooperating centre.
Who cannot join
- 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).
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- 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:
- chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose (≤ 10 mg methylprednisolone or equivalent).
- sex hormones. Prior treatment must be stopped before study entry.
- other experimental drugs or any other anti-cancer therapy.
- Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
- Male patients.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the detailed description
Primary objectives:
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.
Secondary objectives:
To determine the rates of ypT0 ypN0; ypT0; ypT0/is; ypN0; and regression grades according to Sinn.
To determine the response rates of the breast tumor and axillary nodes by physical examination and imaging tests (sonography, mammography, or MRI) after 6 weeks of the 2 anti-HER2 agents alone and at surgery.
To determine the breast and axilla conservation rate after treatment. To assess the toxicity and compliance. To correlate skin toxicity and diarrhoea with pCR. To examine and compare pre-specified molecular markers such as EGFR, HER2, HER3, HER4, TGFß, EGF, AREG, HBEGF, BTC, EPIGEN, EREG, NRG1, NRG2, neuroglycan, tomoregulin, NRG4 and NRG3K-RAS, MET, IGF1R, IRS1, PTEN, FGFR1, FGFR2, FGFR3, AXL, RET, and PDGFR; EGFR signature, Ki67, p95HER2, and PI3K mutation before start of afatinib+trastuzumab, before and after chemotherapy.
- Conditions
- Unilateral HER2 Positive Breast Cancer
- Being tested
- Afatinib, Trastuzumab, Paclitaxel, Epirubicin, Cyclophosphamide
- Keywords
- DAFNE, GBG 70, GBG, German Breast Group, GBG Forschungs GmbH, Afatinib, neo-adjuvant, HER-2 positive breast cancer, BIBW 2992, 1200.159
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AfatinibDrug
20 mg daily for 17 weeks (first two weeks every second day).
TrastuzumabDrug
Also called HERCEPTIN
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).
PaclitaxelDrug
80 mg/m² i.v. given weekly on day 1 q day 8 for 12 weeks.
EpirubicinDrug
90 mg/m² i.v. given on day 1 q day 22 for 4 cycles.
CyclophosphamideDrug
600 mg/m² i.v. given on day 1 q day 22 for 4 cycles.
| Study group | Role | What they receive |
|---|---|---|
| Treatment arm | Experimental | Afatinib-Trastuzumab (6 weeks) followed by Afatinib*-Paclitaxel-Trastuzumab (12 weeks) followed by Epirubicin-Cyclophosphamide-Trastuzumab (12 weeks). *only 11 weeks. Receives: Drug: Afatinib; Drug: Trastuzumab; Drug: Paclitaxel; Drug: Epirubicin; Drug: Cyclophosphamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 30 weeks
Secondary outcomes (6)
Pathological Complete Response
To determine the rates of ypT0 ypN0; ypT0; ypT0/is; ypN0; and regression grades according to Sinn.
Measured: 30 weeks
Response Rate by Physical Examination and Imaging Tests
To determine the response rates of the breast tumor and axillary nodes by physical examination and imaging tests (sonography, mammography, or MRI) after 6 weeks of the 2 anti-HER2 agents alone and at surgery.
Measured: 30 weeks
Conservation Rate
To determine the breast and axilla conservation rate after treatment.
Measured: 30 weeks
Number of Participants with (Serious) Adverse Events as a Measure of Safety and Tolerability
Analysis of number and grading of (serious) adverse events during the different treatment phases.
Measured: 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
Analysis of number and grading of skin toxicity and diarrhea as (serious) adverse events in correlation with pCR.
Measured: 30 weeks
Translational Research
To examine and compare pre-specified molecular markers such as EGFR, HER2, HER3, HER4, TGFß, EGF, AREG, HBEGF, BTC, EPIGEN, EREG, NRG1, NRG2, neuroglycan, tomoregulin, NRG4 and NRG3K-RAS, MET, IGF1R, IRS1, PTEN, FGFR1, FGFR2, FGFR3, AXL, RET, and PDGFR; EGFR signature, Ki67, p95HER2, and PI3K mutation before start of afatinib+trastuzumab, before and after chemotherapy.
Measured: 30 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 May 2012 (estimated)
- Study startMay 2012
- Primary completionMar 2014
- Study completionMar 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Unilateral HER2 Positive Breast CancerStudies of the same condition, open and under way.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 65 participants (actual)
Sponsor and investigators
- Lead sponsor
- GBG Forschungs GmbH
- Sponsor type
- University, hospital or other
- Collaborators
- Boehringer Ingelheim
- Responsible party
- Sponsor
- Investigators
- Claus A Hanusch, MD, PhD, Principal investigator, Rotkreuzklinikum München, 80634 München, Rotkreuzplatz 8
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01594177
- Sponsor's protocol ID
- GBG 70
- Other IDs
- 2011-004704-38
- Acronym
- DAFNE
- Status last verified
- Mar 2014
- First submitted
- 3 May 2012
- Last updated
- 13 Mar 2014
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 13 Mar 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dual Blockage With Afatinib and Trastuzumab as Neoadjuvant Treatment for Patients With Locally Advanced or Operable Breast Cancer Receiving Taxane-anthracycline Containing Chemotherapy
- ClinicalTrials.gov ID
- NCT01594177
- Acronym / sponsor ID
- DAFNE / GBG 70
- 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
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 65 participants (actual)
- Lead sponsor
- GBG Forschungs GmbHUniversity, hospital or other
- Collaborators
- Boehringer Ingelheim
- Study start
- May 2012
- Primary completion
- Mar 2014 (actual)
- Study completion
- Mar 2014 (actual)
- First posted
- 8 May 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Primary objectives:
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.
Secondary objectives:
To determine the rates of ypT0 ypN0; ypT0; ypT0/is; ypN0; and regression grades according to Sinn.
To determine the response rates of the breast tumor and axillary nodes by physical examination and imaging tests (sonography, mammography, or MRI) after 6 weeks of the 2 anti-HER2 agents alone and at surgery.
To determine the breast and axilla conservation rate after treatment. To assess the toxicity and compliance. To correlate skin toxicity and diarrhoea with pCR. To examine and compare pre-specified molecular markers such as EGFR, HER2, HER3, HER4, TGFß, EGF, AREG, HBEGF, BTC, EPIGEN, EREG, NRG1, NRG2, neuroglycan, tomoregulin, NRG4 and NRG3K-RAS, MET, IGF1R, IRS1, PTEN, FGFR1, FGFR2, FGFR3, AXL, RET, and PDGFR; EGFR signature, Ki67, p95HER2, and PI3K mutation before start of afatinib+trastuzumab, before and after chemotherapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment arm | Experimental | Drug: Afatinib, Drug: Trastuzumab, Drug: Paclitaxel, Drug: Epirubicin, Drug: CyclophosphamideAfatinib-Trastuzumab (6 weeks) followed by Afatinib*-Paclitaxel-Trastuzumab (12 weeks) followed by Epirubicin-Cyclophosphamide-Trastuzumab (12 weeks). *only 11 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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.
Key exclusion criteria (20 listed)
- 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.
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 |
|---|---|---|
| Afatinib20 mg daily for 17 weeks (first two weeks every second day). | Drug | Treatment arm |
| TrastuzumabAlso: HERCEPTINFirst 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). | Drug | Treatment arm |
| Paclitaxel80 mg/m² i.v. given weekly on day 1 q day 8 for 12 weeks. | Drug | Treatment arm |
| Epirubicin90 mg/m² i.v. given on day 1 q day 22 for 4 cycles. | Drug | Treatment arm |
| Cyclophosphamide600 mg/m² i.v. given on day 1 q day 22 for 4 cycles. | Drug | Treatment arm |
Primary outcome
Pathological Complete Response
Time frame: 30 weeks
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.
6 secondary outcomes
Pathological Complete Response
Time frame: 30 weeks
Response Rate by Physical Examination and Imaging Tests
Time frame: 30 weeks
Conservation Rate
Time frame: 30 weeks
Number of Participants with (Serious) Adverse Events as a Measure of Safety and Tolerability
Time frame: 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
Time frame: 30 weeks
Translational Research
Time frame: 30 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Mar 2014.
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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.
Claus A Hanusch, MD, PhD principal investigator
Rotkreuzklinikum München, 80634 München, Rotkreuzplatz 8
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Afatinib, Trastuzumab and Paclitaxel in people with Unilateral HER2 Positive Breast Cancer, run by GBG Forschungs GmbH at 1 site in Germany.
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 21 inclusion and 20 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 13 Mar 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. 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 phase mean?
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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Pathological Complete Response (time frame: 30 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 13 Mar 2014.