Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Paclitaxel

Albumin-Bound Paclitaxel

Taxane

Tubulin Modulators

Antimitotic Agents

Nab-Paclitaxel 125 mg/m2 i.v. over 30 min. weekly in 5 out of 6 weeks

Given until progression, unacceptable toxicity, patient's request or withdrawal from Study

Nab-Paclitaxel

Nab-paclitaxel has demonstrated to be an active agent in breast cancer and probably a less toxic alternative to solvent based taxanes. It is indicated in metastatic breast cancer after failure of anthracyclines. However, most patients receive anthracyclines as well as taxanes as part of their (neo-)adjuvant therapy. There is currently no standard treatment for patients with an early relapse (\<12 months) after a taxane containing (neo-)adjuvant therapy. Nab-paclitaxel, a novel nano-particle encapsulated paclitaxel is expected to have only limited cross-resistant to solvent-based taxanes and might therefore be indicated in this setting.

Primary Objective:

To determine overall response rate (ORR) and to exclude that it is 20% or lower.

Secondary Objectives:

1. To determine compliance and toxicity of the therapy.
2. To determine clinical benefit rate (CBR) in patients with measurable disease.
3. To determine duration of response.
4. To determine progression-free survival (PFS).
5. To determine overall survival.
6. To assess biomarkers, e.g. SPARC expression in the tissue of the primary or metastatic tumor.

Nab-paclitaxel in Metastatic Breast Cancer Patients Failing Solvent Based Taxane (Tiffany)

A Multicenter Non-randomized Phase II Study to Evaluate Nab-paclitaxel in Metastatic Brest Cancer Patients Failing a Solvent Based Taxane as (Neo-)Adjuvant Treatment (Tiffany)

Number and percent of patients with Adverse Events (any Grade and Grade 3/4).

Number and percent of the patients with treatment modifications (dose delay / dose reduction / premature dicontinuation)

German Breast Group

Rare Diseases

Carcinoma, Ductal, Breast

Inflammatory Breast Neoplasms

Carcinoma

Carcinoma, Ductal

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Inflammatory Breast Cancer

Antirheumatic Agents

Cyclophosphamide

Epirubicin

Pertuzumab

nab-Paclitaxel (125 mg/m² weekly, infusion) is applicated for 12 weeks, followed by epirubicin and cyclophosphamide, applicated 4 cycles 3-weekly . In case of HER2-positive tumor patients receive tarstuzumab and pertuzumab 3-weekly during all cycles.

Paclitaxel (80 mg/m² weekly, infusion) is applicated for 12 weeks, followed by epirubicin and cyclophosphamide, applicated 4 cycles 3-weekly . In case of HER2-positive tumor patients receive tarstuzumab and pertuzumab 3-weekly during all cycles.

nab-Paclitaxel 125 mg/m² weekly for 12 weeks

nab-Paclitaxel

Michael Untch, Prof MD

Current guidelines as those from the AGO-Breast commission recommend for neoadjuvant breast cancer patients either a sequence of 4 cycles EC followed by 4 cycles of a taxane or 6 cycles of TAC based on previous large scale studies.

Treatment of patients with HER2-positive disease should include also simultaneous application of trastuzumab.

Solvent-based taxanes (paclitaxel, docetaxel) cause severe toxicities not only by the active agents itself but also by the solvents like cremophor. Nab-paclitaxel (Abraxane®) is a solvent-free formulation of paclitaxel encapsulated in albumin. It does not require premedication with corticosteroids or antihistamines to prevent the risk of solvent-mediated hypersensitivity reactions. This new formulation improves safety profile, allows higher dosing with shorter infusion duration, and produces higher tumor drug concentration.

As neoadjuvant treatment does not only allow to compare competing treatment approaches with a very high quality (homogenous treatment population, precise assessment of response by histological assessment), but also to identify predictive markers, this trial will compare weekly nab-paclitaxel with solvent-based paclitaxel at their currently optimal doses.

In case of HER2-positive tumor status patients receive Pertuzumab and Trastuzumab additionally.

Primary Objectives:

To compare the pathological complete response (pCR=ypT0 ypN0) rates of neoadjuvant treatment of nab-paclitaxel with solvent-based paclitaxel as part of neoadjuvant treatment of operable or locally advanced primary breast cancer

Secondary Objectives:

* To assess the pCR rates per arm separately for the stratified subpopulations.
* To determine the rates of ypT0/is ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0; and regression grades.
* To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) after treatment in both arms.
* To assess clinical response rate after taxane in both groups
* To determine the breast conservation rate after each treatment.
* To assess the toxicity and compliance.
* To assess the time of onset of grade 3 neuropathy
* To assess the time of resolution of grade 3/4 neuropathy to at least grade 1
* To determine loco-regional invasive recurrence free survival (LRRFS), distant-disease-free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS) in both arms and according to stratified subpopulations.
* To assess regional recurrence free survival (RRFS) in patients with initial node-positive axilla converted to negative at surgery and treated with sentinel node biopsy alone.
* To determine the pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy before surgery.
* To examine and compare pre-specified molecular markers such as SPARC, gp60, calveoline 1 and other markers potentially differentially predicting efficacy of nab-paclitaxel and solvent-based paclitaxel on core biopsies before, during and after chemotherapy.

Objectives of Substudies:

* To assess, characterize, and correlate circulating tumor cells and proteins with the effect of treatment (CTC Substudy).
* To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect (Pharmacogenetic substudy)
* To assess ovarian function measured by amenorrhea rate in correlation with changes in E2, FSH, LH , Anti-Müller Hormone, ultrasound-follicle count in patients aged \< 45 years.

Nanoparticle-based Paclitaxel vs Solvent-based Paclitaxel as Part of Neoadjuvant Chemotherapy for Early Breast Cancer (GeparSepto)

A Randomized Phase III Trial Comparing Nanoparticle-based Paclitaxel With Solvent-based Paclitaxel as Part of Neoadjuvant Chemotherapy for Patients With Early Breast Cancer (GeparSepto)

No microscopic evidence of residual invasive or non-invasive viable tumor cells in all resected specimens of the breast and axilla.

Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries.

The primary endpoint will be summarized as pathological complete remission rate for each treatment group.

Response (by physical examination, imaging response, breast conservation) will also be summarized as rates in each treatment group.

To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) after treatment in both arms.

Descriptive statistics for the 4 treatments (each taxane +/- anti-HER2-treatment) will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped.

To assess clinical response rate after taxane in both groups.

To determine the breast conservation rate after each treatment.

To assess the time of onset of grade 3 neuropathy.

To assess the time of resolution of grade 3/4 neuropathy to at least grade 1.

To assess regional recurrence free survival (RRFS) in patients with initial node-positive axilla converted to negative at surgery and treated with sentinel node biopsy alone.

To determine the pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy before surgery.

To examine and compare pre-specified molecular markers such as SPARC, gp60, calveoline 1 and other markers potentially differentially predicting efficacy of nab-paclitaxel and solvent-based paclitaxel on core biopsies before, during and after chemotherapy.

The aim is to identify potential predictive short and long term parameters.

To assess, characterize, and correlate circulating tumor cells and proteins with the effect of treatment.

To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect.

To assess ovarian function measured by amenorrhea rate in correlation with changes in E2, FSH, LH , Anti-Müller Hormone, ultrasound-follicle count in patients aged \<45 years.

LRRFS is defined as the time period between registration and first event and will be analyzed after the end of the study by referring to data from GBG patient's registry.

DDFS is defined as the time period between registration and first event and will be analyzed after the end of the study by referring to data from GBG patient's registry.

IDFS is defined as the time period between registration and first event and will be analyzed after the end of the study by referring to data from GBG patient's registry.

OS is defined as the time period between registration and first event and will be analyzed after the end of the study by referring to data from GBG patient's registry.

If it can be shown at an interim analysis that the positive predictive value for a pCR of a negative (\>=3) core biopsies before surgery in patients with complete clinical response is \>90%, these patients might opt for having no further breast surgery.

Celgene Corporation

Roche Pharma AG

Amino Acids

Trastuzumab

Carboplatin

Bevacizumab

Lapatinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Carboplatin AUC 2 min/mL weekly, infusion will be used as Add-on to the background therapy (same as comparator arm)

background treatment with NLPD (Myocet), Paclitaxel, Herceptin (Trastuzumab fpr Her2 pos), Tyverb (Lapatinib for Her2 pos), Avastin (Bevacizumab for triple negative) agents are used according to marketed formulation via normal procedures at each site and applied according to recommendations of the manufacturers.

Carboplatin, AUC, 2 min/mL weekly, infusion

background treatment according to standards fpr triple negative and Her2pos breast cancer patients Paclitaxel: 80 mg/m² i.v. given weekly on day 1 q day 8 for 18 weeks. NPLD (Myocet®): 20 mg/m² weekly on day 1 q day 8 for 18 weeks Trastuzumab (only for HER2-positive patients): Loading dose: 8 mg/kg, Maintenance dose: 6 mg/kg, day 1 q day 22 for 6 cycles. Post-surgery: up to a total duration of 1 year according to current AGO guidelines Lapatinib 750 mg/day p.o. continuously for 18 weeks; in case of good tolerability (no CTC grade II toxicity except alopecia and nausea/vomiting) during the first cycle the dose may be escalated to 1000 mg.

Bevacizumab: 15 mg/kg i.v., day 1 q day 22 for 6 cycles (only in TNBC patients).

background treatment

Gunter von Minckwitz, MD, Prof

Study participants with primary breast cancer will receive a standard chemotherapy with an anthracycline and a taxane as well as trastuzumab in case of HER2-positive tumors at doses and duration in concordance to current treatment guidelines. Patients will be receive and benefit in addition currently not in the neoadjuvant setting registered medication as lapatinib or bevacizumab of which significant increases of cure (pCR) rates have been reported in previous phase III studies. Patients randomized to carboplatin will receive in addition to the described backbone therapies a potentially active agent which suggested synergy of efficacy with chemotherapies as well as targeted agents. Patients might have the risk of an increase in toxicities due to the added agents and will have additional burden due to investigations required for study participation. However, due to the severity of the underlying disease and the high risk of relapse and death due to the stage of disease, this increase in toxicity and burden appears less relevant compared to the potential higher efficacy and finally cure rate by the incorporated treatments.

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 to chemotherapy. Recent data from the Neo-Altto and Neosphere trials suggest that a dual blockage of the HER2 receptor with e.g. trastuzumab and lapatinib reach significantly higher pCR rates than trastuzumab alone and should therefore represent the treatment back-bone of new neoadjuvant trials. A preplanned subgroup analysis of the GeparQuinto study demonstrated that in TNBC the addition of bevacizumab resulted in a significant increase of pCR rates (HR 1.4).

Having a better cardiac tolerability profile compared to conventional anthracyclines, the non-pegylated liposomal encapsulated doxorubicin (NPLD) Myocet® might provide the possibility to combine taxane, anthracycline, platinum salt as well with targeted agents as double HER2 blockage or bevacizumab.

Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer

A Randomized Phase II Trial Investigating the Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer

Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries. Surgery takes place shortly after the 18 weeks (six 3-week cycles) chemotherapy treatment. No microscopic evidence of residual viable tumor cells in all resected specimens of the breast and axilla meets the primary endpoint.

To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests. (sonography, mammography, or MRI) after treatment in both arms.

LRRFS, RRFS, LRFS, DDFS, IDFS and OS are defined as the time period between registration and first event and will be analyzed after the end of the study by referring to data from GBG patient's registry.

Tolerability and Safety: Descriptive statistics for the 4 treatments will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped

• To assess the pCR rates per arm separately in patients with triple-negative tumors and HER2-positive tumors.

To determine the breast and axilla conservation rate after each treatment.

To assess the pCR rate in patients with a clinical complete response and a negative core biopsy before surgery.

To examine and compare pre-specified molecular markers such as BRCA1-mRNA, P53, ALDH1, p4E-BP1, IL-8 metagene, B-Cell metagene as well as exploratory analyses and lymphocyte infiltration on core biopsies before and surgical tissue after end of chemotherapy. The aim is to identify potential predictive short and long term parameters.

To assess ovarian function measured by amenorrhea rate in correlation with changes in E2, FSH, Anti-Müller Hormone, ultrasound-follicle count in patients aged \<45 years.

Teva Pharmaceuticals USA

GlaxoSmithKline

Cabazitaxel 25 mg/m² i.v. (Day 1) every 3 weeks (cycle) as 1-hour i.v infusion for a total of up to 4 cycles over a maximum total treatment period of 15 weeks before surgery

Cabacitaxel

Paclitaxel 80 mg/m² as 1-hour i.v infusion. Patients will receive weekly (Days 1, 8, 15) paclitaxel administrations for a maximum of 12 infusions for a maximum of 4 cycles over a maximum total treatment period of 15 weeks before surgery (1 cycle = 3 weeks).

Gunter von Minckwitz, Prof. Dr.

Cabazitaxel is a new taxoid which promotes the tubulin assembly in vitro and stabilizes microtubules against cold-induced depolymerization as efficiently as docetaxel and was selected for development based on a better antiproliferative activity on resistant cell lines than docetaxel. It has shown superior survival against mitoxantrone (MTX) plus prednisone in docetaxel pre-treated hormone refractory metastatic prostate cancer patients leading to registration of the compound. It showed a favorable toxicity profile with an interestingly low rate of alopecia. In the Genevieve study it will be compared against weekly paclitaxel which is currently most widely used treatment of breast cancer patients. A head-to-head comparison in the neoadjuvant setting will allow a rapid and precise comparison of efficacy and tolerability of cabacitaxel versus paclitaxel to decide in how far further development of this taxoid in breast cancer is reasonable.

Primary Objective To compare the pathologic complete response (pCR) rate in the breast (ypT0/is ypN0/+) in patients with operable Triple Negative or luminal B/HER2 normal breast cancer treated with either cabazitaxel or weekly paclitaxel.

Secondary Objective To assess

* pCR rates per arm separately for the stratified subpopulations.
* Objective response rate (ORR) in the breast according to WHO criteria.
* pCR rate defined as ypT0 ypN0.
* pCR rate defined as ypT0/is ypN0.
* pCR rate in the axillary lymph nodes (ypN0).
* To determine the pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy before surgery.
* Breast conservation surgery rate.
* To assess the toxicity (NCI CTCAE V4.03) and compliance in both arms.
* Invasive loco-regional recurrence free survival (LRRFS), distant-disease-free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS).
* To explore the biomarkers and profiles potentially predicting response to treatment.

Efficacy and Safety of Cabazitaxel Versus Weekly Paclitaxel as Neo-adjuvant Treatment in Patients With Triple Negative or Luminal B/HER2 Normal BC (GENEVIEVE)

Randomized, Open-label, Phase II Study Comparing the Efficacy and the Safety of Cabazitaxel Versus Weekly Paclitaxel Given as Neo-adjuvant Treatment in Patients With Operable Triple Negative or Luminal B/HER2 Normal Breast Cancer (GENEVIEVE)

pathologic complete response (pCR) rate separately for stratified subpopulations

To determine the pCR rate in patients with a clinical complete response (cCR) and a negative core biopsy before surgery

To determine the local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy before surgery

To assess the toxicity (NCI CTCAE V4.03) in both arms.

Capecitabine

Antimetabolites

Patients will receive pazopanib tablets once daily at a dose according to the allocated dose level:

* dose level I: 400 mg
* dose level II: 600 mg
* dose level III: 800 mg

In addition patients receive capecitabine at the same oral dose for all dose levels with 1600 mg/m2 on days 1 to 14 every 3 weeks.

Treatment will be given until disease progression or unacceptable toxicity of the study drug, or withdrawal of consent of the patient.

Six patients will be recruited in each dose level. If less than 2 out of 6 patients experience a DLT within the first 2 cycles (weeks 1 to 6), the next dose level is started. Once the MTD is established, additional 6 patients will be included into this dose level to further characterise the safety of the dose regimen.

If it is reported, that two patients had a DLT, all patients are informed about it and the dose level immediately reduced by one dose level.

Pazopanib plus capecitabine

Angiogenesis is essential for the growth of large tumor. A number of anti-angiogenic agents are currently under development. Bevacizumab, a humanised monoclonal antibody to vascular endothelial growth factor (VEGF), has been shown to improve disease free survival in first line metastatic breast cancer when associated with chemotherapy 1. Results of a randomised phase II trial combining sorafenib, a tyrosine kinase inhibitor targeting multiple tyrosine kinases including VEGFR1, VEGFR2, VEGFR3, with capecitabine have recently been reported 2. Compared to capecitabine plus placebo, progression-free survival in the capecitabine + sorafenib arm was significantly increased from 4.1 months to 6.4 months. Toxicities were also increased, with an incidence rate of grade 3/4 hand foot syndrome of 45% in the capecitabine + sorafenib arm compared to 13% in the capecitabine + placebo arm. The increased toxicity will most likely limit the clinical use of this regimen.

Pazopanib is a potent, multi-targeted TKI of VEGFR-1, -2, -3, PDGFR-α and -β and c-kit and has recently been approved for the treatment of renal cell cancer in the U.S. In the EU, a positive opinion has been issued by the European Medicines Agency.

A phase II study of GW786034 (pazopanib) in patients with recurrent or metastatic invasive breast carcinoma included 19 patients after a maximum of 2 lines of chemotherapy for advanced disease 3. Pazopanib 800 mg daily was given continuously.

A clinically significant rate of stable disease (58%) was detected with a median TTP of 5.3 months (95% CI: 1.8 - 9.0 months). Four patients treated with pazopanib had SD for ≥ 6 months, for a clinical benefit rate (CBR), defined as rate of SD for ≥ 6 months or CR or PR, of 5/19 (26%), which is at least comparable to sunitinib and bevacizumab (CBR 16% and 17%, respectively).

The pivotal study of full dose (800 mg) daily pazopanib in renal cell cancer reported hand foot syndrome of all grades in only 6% of patients 4. The optimally tolerated regimen (OTR) of pazopanib was determined when administered in combination with capecitabine and oxaliplatin in patients with advanced CRC 5. In patients who received capecitabine (850 mg twice daily) plus 800 mg once daily pazopanib combined with oxaliplatin, the incidence of hand foot syndrome of all grades was 24%.

The present study will investigate the combination of pazopanib and capecitabine in advanced or metastatic breast cancer with the aim to develop a new treatment option with increased efficacy and tolerability.

Primary Objective:

To assess the maximum tolerated dose (MTD) of pazopanib in combination with capecitabine as treatment for metastatic HER2-negative breast cancer.

Secondary Objective:

1. To determine the dose-limiting toxicity (DLT).
2. To determine the compliance and toxicity of the combination.
3. To determine the objective response rate (ORR) and clinical benefit rate (CBR) in patients with measurable disease.
4. To determine the duration of response.
5. To determine the progression-free survival (PFS).
6. To determine the predictive value for response of serum markers such as VEGF.

Pazopanib in Combination With Capecitabine in Patients With Metastatic Breast Cancer

Phase I Study to Assess the Optimal Dose for Pazopanib in Combination With Capecitabine in Patients With HER2-negative, Metastatic Breast Cancer (PazoX)

The maximum tolerated dose (MTD) is defined as the highest dose level with DLT in no more than 1 out of 6 patients. A maximal tolerated dose (MTD) could not be established.

To determine the objective response rate (ORR) in patients with measurable disease. ORR consists of complete response and partial response according to the RECIST criteria. Complete Response refers to the disappearance of all target lesions. Any pathological lymph nodes must have a reduction in short axis to less than 10 mm. Partial Response refers to an at least 30 percent decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

To determine the clinical benefit rate (CBR) in patients with measurable disease. CBR consists of complete response , partial response, and stable disease lasting greater than 24 weeks. All patients are included when determining this rate. 2 patients were on study treatment for a long time.Hence the outcome rate of 25 percent ( 2 from 8 patients)

There was only one arm in this study as this was a dose escalation study.

Pazopanib Plus Capecitabine

premenopausal

Postmenopausal

Age, Customized

Sex: Female, Male

ECOG 0

ECOG 1

ECOG Status refers to the Eastern Cooperative Oncology Group scale . These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis...Grade 0 Fully active

* Grade 1 restricted in physically strenuous activity
* Grade 2 Ambulatory and capable of all selfcare
* Grade 3 Capable of only limited selfcare
* Grade 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
* Grade 5 Dead

ECOG

T status describes the size of the original (primary) tumor and whether it has invaded nearby tissue,,,T1 - The tumour is 2 centimetres (cm) across or less...T2 - The tumour is more than 2 centimetres, but no more than 5 centimetres across...T3 - The tumour is bigger than 5 centimetres across...T4 refers to inflamatory breast cancer....Tis means DCIS(ductal carcinoma in situ...The tumors are all breast cancer tumors as the study has to do with breast cancer.

T status

N status is a categorisation of the number of lymph nodes..N0 - No cancer cells found in any nearby nodes...N1 is when 1 to 3 lymph nodes are found.....N2 is when 4 to 9 lymph nodes are found....N2 is when greater than 9 lymph nodes are found

N Status

Grading is a measure of the cell appearance in tumors and other neoplasms in pathology...Grade 1 Well differentiated (Low grade)...

Grade 2 Moderately differentiated (Intermediate grade)... Grade 3 poorly differentiated (High grade)

Grading

ERneg/PRneg

ERneg/PRpos

ERpos/PRneg

ERpos/PRpos

Hormone Receptor Status

Her2 Negative

Her2 Positive

HER2 Status

Dr. Andreas Schneeweiss

A maximal tolerated dose (MTD) could not be established. The study was stopped after 8 patients.

Maximum Tolerable Dose (MTD) of Pazopanib

The following DLTs resulted in permanent discontinuation of the study therapy: hypertension, (DLT 1), mucositis CTC grade 3, hand-foot-syndrome CTC grade 3, increase of liver enzymes (GOT,- and GPT) CTC grade 2 (DLT 2), and increase of liver enzymes (GOT-, GPT) CTC grade 3 (DLT 3).

Dose-limiting Toxicity (DLT)

Anemia Grade 1 to 4

Leucopenia Grade 1 to 4

Number of Cycles

Pazopanib + Capecitabine

Hematological Toxicity of the Combination of Pazopanib and Capecitabine

Hepatotoxicity

Hypertension

Pancreatectomy

Thrombocytopenia

6 patients experience 6 Serious Adverse Reactions

Other Toxicity of the Combination of Pazopanib and Capecitabine

All patients are included when determining this rate.

Objective Response Rate (ORR)

2 patients were on study treatment for a long time.

Clinical Benefit Rate (CBR)

The baseline refers only to the 8 patients who received Pazopanib.

Overall Study

Anti-Infective Agents

Afatinib

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Anti-Bacterial Agents

Antibiotics, Antitubercular

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

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

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).

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

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

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

Claus A Hanusch, MD, PhD

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.

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.

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

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.

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.

Analysis of number and grading of (serious) adverse events during the different treatment phases.

Analysis of number and grading of skin toxicity and diarrhea as (serious) adverse events in correlation 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 title	NCT ID	Conditions	Interventions	Eligibility	Organization
Nab-paclitaxel in Metastatic Breast Cancer Patients Failing Solvent Based Taxane (Tiffany)	NCT01416558	Metastatic Brea...	Nab-Paclitaxel	18 Years -	German Breast Group
Nanoparticle-based Paclitaxel vs Solvent-based Paclitaxel as Part of Neoadjuvant Chemotherapy for Early Breast Cancer (GeparSepto)	NCT01583426	Tubular Breast ... Mucinous Breast... Breast Cancer F... Invasive Ductal... Tubular Breast ... HER-2 Positive ... Inflammatory Br... Inflammatory Br...	nab-Paclitaxel Paclitaxel	18 Years -	German Breast Group
Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer	NCT01426880	Tubular Breast ... Mucinous Breast... Breast Cancer F... Invasive Ductal... Tubular Breast ... HER-2 Positive ... Inflammatory Br... Inflammatory Br...	Carboplatin background trea...	18 Years -	German Breast Group
Efficacy and Safety of Cabazitaxel Versus Weekly Paclitaxel as Neo-adjuvant Treatment in Patients With Triple Negative or Luminal B/HER2 Normal BC (GENEVIEVE)	NCT01779479	Primary Breast ...	Cabacitaxel Paclitaxel	18 Years -	German Breast Group
Nab-paclitaxel in Metastatic Breast Cancer Patients Failing Solvent Based Taxane (Tiffany)	NCT01416558	Metastatic Brea...	Nab-Paclitaxel	18 Years -	German Breast Group
Pazopanib in Combination With Capecitabine in Patients With Metastatic Breast Cancer	NCT01498458	Metastatic Brea...	Pazopanib plus ...	18 Years -	German Breast Group
Dual Blockage With Afatinib and Trastuzumab as Neoadjuvant Treatment for Patients With Locally Advanced or Operable Breast Cancer Receiving Taxane-anthracycline Containing Chemotherapy	NCT01594177	Unilateral HER2...	Afatinib Trastuzumab Paclitaxel Epirubicin Cyclophosphamid...	18 Years -	German Breast Group

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