Phase II Trial to Validate Markers for a Response Evaluation of a Combined Therapy in Patients With HER2+ Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01891357
Recruitment Status : Unknown
Verified August 2015 by West German Study Group.
Recruitment status was:  Recruiting
First Posted : July 3, 2013
Last Update Posted : August 7, 2015
Information provided by (Responsible Party):
West German Study Group

Brief Summary:
The Neo-PREDICT-HER2 Study is phase II trial to validate predictive markers for the response evaluation of a combined chemo-immunotherapy in patients with HER2-positive early breast cancer. The only treatment arm consists of Paclitaxel 80 mg/m2 weekly for 12 weeks with lapatinib 750 mg P.O. daily and trastuzumab 2 mg/kg IV (loading dose 4 mg/kg) weekly for 12 weeks.

Condition or disease Intervention/treatment Phase
Carcinoma, Ductal, Breast Procedure: Biopsy before and after three weeks of study treatment Drug: Paclitaxel Drug: lapatinib Drug: trastuzumab Phase 2

Detailed Description:

Trastuzumab (T)-containing neoadjuvant chemotherapy has been reported to increase the probability of pathological complete response (pCR) in HER2 positive disease up to 67 %. Large trials revealed pCR rates (no remaining invasive and in situ components) of about 30-40 %, if anthracyclines/taxane based polychemotherapy was applied or about 40-45 % if no invasive tumor in the breast and lymph nodes was used as a pCR definition.

Nevertheless, resistance to trastuzumab remains one of the most important challenges in adjuvant and metastatic breast cancer therapy causing poor prognosis with an increased incidence of cerebral metastasis and limited therapeutic options after disease progression6. An improvement shows the combination of trastuzumab and lapatinib, which has been reported to have increased efficacy in in-vitro and in metastatic setting in patients who were mostly resistant to both therapies in the previous course of disease. Recent data from the neoadjuvant setting (neoALTTO) - on a paclitaxel backbone - showed a significantly higher pCR rate after L + T than with either compound separately (47 % vs. 20 % and 27.6 % respectively). Several trials are planned to evaluate the combination of both therapies in the adjuvant and neoadjuvant setting.

Clinical response measured by sequential evaluation of different proliferation markers (such as Ki-67) following a course of neoadjuvant chemotherapy has been demonstrated to correlate significantly with an increased risk of relapse in patients not achieving pathological complete response. It is therefore clinically relevant to evaluate such proliferation tools for early prediction of combination therapy efficacy (chemotherapy and HER2 targeted therapy). So far, it remains unclear which method of proliferation measurement is the optimal marker for response evaluation regarding a combined chemo-immunotherapy. However, measurement of proliferation and apoptosis genes as well as assessment of changes in Phosphatidylinositol 3-kinases (PI3K), Protein Kinase B (AKT), Insulin-like Growth Factor (IGF) and stem cell signalling after a short course of therapy could provide a unique signature for a dynamic response evaluation.

The planned trial will validate predictive markers and a dynamic model based on the sequential evaluation of different proliferation and apoptosis markers. Furthermore it will assess the pCR-rate after 12 weeks of therapy. The aim of the study is to define a predictive marker for the response evaluation of a combined chemo-immunotherapy.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter Site, Open Label, Phase II Trial to Validate Predictive Markers for the Response Evaluation of a Combined Chemo-immunotherapy in Patients With HER2-positive Early Breast Cancer
Study Start Date : June 2013
Estimated Primary Completion Date : December 2015
Estimated Study Completion Date : December 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Paclitaxel + Lapatinib + Trastuzumab
Paclitaxel 80 mg/m2 weekly for 12 weeks with lapatinib 750 mg P.O. daily and trastuzumab 2 mg/kg IV (loading dose 4 mg/kg) weekly for 12 weeks, biopsy before and after three weeks of study treatment
Procedure: Biopsy before and after three weeks of study treatment
Core biopsies for histological analyses, to be analysed by the central pathology

Drug: Paclitaxel
Drug: lapatinib
Drug: trastuzumab

Primary Outcome Measures :
  1. Pathological complete response (pCR) [ Time Frame: Average of 16 weeks ]

Secondary Outcome Measures :
  1. Event free survival (EFS) [ Time Frame: 5-year survival ]
  2. Overall Survival (OS) [ Time Frame: 5-year survival ]

Other Outcome Measures:
  1. Proliferation and apoptosis genes [ Time Frame: One week before and after three weeks of treatment ]
    Proliferation Ki-67, Aurora A Kinase (STK15), survivin, Myb-related protein B (MYBL2),Cyclin B1 and apoptosis genes Bcl2, Epidermal Growth Factor-like 2 (SCUBE2), cleaved caspase C3 will be assessed in the samples from diagnostic and sequential biopsy.

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Female patients, age at diagnosis 18 - 75 years
  2. Histological confirmed unilateral primary invasive carcinoma of the breast
  3. Clinical Stage Tumor 1 (cT1) (> 1 cm) - Clinical Stage Tumor 4 (cT4) (if operable, inflammatory breast cancer is excluded)
  4. HER2 over-expressing tumor confirmed by: 3+ by Immuno-histochemistry (IHC) and/or HER2/neu gene amplification by fluorescence, chromogenic or silver in-situ hybridization [Fluorescent In-Situ Hybridization (FISH), Chromogenic In-Situ Hybridization (CISH) or Silver In-Situ Hybridization (SISH); > 6 HER2 gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥ 2.0]
  5. Clinically node positive disease or node negative disease
  6. No clinical evidence for distant metastasis (cM0) after conventional staging
  7. Performance Status Eastern Cooperative Oncology Group (ECOG) ≤ 1 or Karnofsky Index (KI) ≥ 80%
  8. Baseline Left Ventricular Ejection Fraction (LVEF) > 50% measured by echocardiography
  9. Negative pregnancy test (urine or serum) within 7 days prior to start of induction treatment in premenopausal patients
  10. The patient must be accessible for treatment and follow-up
  11. Written informed consent including a written informed consent for shipping of tumor block for central pathology review and evaluation prior to the start of any study procedures

Exclusion Criteria:

  1. Known hypersensitivity reaction to the compounds or incorporated substances
  2. Known polyneuropathy grade ≥ 2
  3. Have acute or currently active or requiring anti-viral therapy hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, stable chronic liver disease per investigator assessment).
  4. Prior malignancy with a disease-free survival of < 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri
  5. Prior or concurrent treatment with cytotoxic agents for any reason after consultation with the sponsor
  6. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry
  7. Male breast cancer
  8. Concurrent pregnancy; patients of childbearing potential must implement a highly effective (less than 1% failure rate) non-hormonal contraceptive measures during the study treatment
  9. Breast feeding women
  10. Sequential breast cancer
  11. Lack of patient compliance
  12. Inadequate organ function including:

    • Leucocytes < 3.5 x 109/l
    • Platelets < 100 x 109/l
    • Absolute Neutrophil Count (ANC) < 1.5 x 109/l
    • Hemoglobin < 9 g/dl
    • Serum Creatinine > 1.5 mg/dl
    • Serum Bilirubin > 1.1 mg/dl
    • Alkaline phosphatase > 2.5 x Upper Limit of Normal (ULN)
    • Aspartate Transaminase (ASAT) and/or Alanine Transaminase (ALAT) > 2.5 ULN
    • Albumin < 2.5 g/dl
  13. Uncompensated cardiac function
  14. Malabsorption syndrome, disease significantly affecting gastrointestinal function
  15. Concomitant use of Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01891357

Contact: Mathias Warm, MD +49 221 8907 ext 6707

Klinikum Esslingen Recruiting
Esslingen, Baden-Württemberg, Germany, 73730
Contact: Thorsten Kühn, MD    +49 711 3103 ext 3051      
Contact: Angelika Jursik    +49 711 3103 ext 3064   
Principal Investigator: Thorsten Kühn, MD         
SLK Kliniken Recruiting
Heilbronn, Baden-Württemberg, Germany, 74078
Contact: Reinhard Hackenberg, MD    +49 7131 4934 ext 00      
Principal Investigator: Reinhard Hackenberg, MD         
Klinikum Frankfurt Höchst Recruiting
Frankfurt (Main), Hessen, Germany, 65929
Contact: Volker Möbus, MD    +49 69 3106 ext 2339   
Principal Investigator: Volker Möbus, MD         
Niels-Stensen-Kliniken Recruiting
Georgsmarienhütte, Niedersachsen, Germany, 49124
Contact: Albert von der Assen, MD    +49 541 502 ext 2275      
Principal Investigator: Albert von der Assen, MD         
Klinikum Westfalen GmbH - Knappschaftskrankenhaus Recruiting
Dortmund, Nordrhein-Westfalen, Germany, 44309
Contact: Markus Skrobol, MD         
Contact: Anna Moik    +49 231 9221 ext 078   
Principal Investigator: Markus Skrobol, MD         
Bethesda Krankenhaus, Senologie Recruiting
Duisburg, Nordrhein-Westfalen, Germany, 47053
Contact: Björn Wieland Lisboa, MD    +49 203 6008 ext 1270   
Principal Investigator: Björn Wieland Lisboa, MD         
St. Barbara-KIinik Recruiting
Hamm, Nordrhein-Westfalen, Germany, 59073
Contact: Herrmann Wiebringhaus, MD         
Contact: Scharnewski Christiane    +49 2381 68123 ext 52   
Principal Investigator: Hermann Wiebringhaus, MD         
Krankenhaus Köln Holweide, Brustzentrum Recruiting
Köln, Nordrhein-Westfalen, Germany, 51067
Contact: Mathias Warm, MD    +49 221 8907 ext 6707   
Principal Investigator: Mathias Warm, MD         
Klinikum Chemnitz gGmbH Recruiting
Chemnitz, Sachsen, Germany, 09116
Contact: Nikos Fersis, MD    +49 371 333 ext 22200      
Principal Investigator: Nikos Fersis, MD         
Praxis für gynäkologische Onkologie am Brustzentrum City Recruiting
Berlin, Germany, 10713
Contact: Lidia Perlova-Griff, MD         
Contact: Michaela Platzer    +49 30 8272 ext 29840   
Principal Investigator: Lidia Perlova-Griff, MD         
Sponsors and Collaborators
West German Study Group
Principal Investigator: Mathias Warm, MD Krankenhaus Köln Holweide

Responsible Party: West German Study Group Identifier: NCT01891357     History of Changes
Other Study ID Numbers: WSG-AM07 (Neo-PREDICT-HER2)
2012-003679-21 ( EudraCT Number )
First Posted: July 3, 2013    Key Record Dates
Last Update Posted: August 7, 2015
Last Verified: August 2015

Keywords provided by West German Study Group:
Unilateral primary invasive carcinoma of the breast

Additional relevant MeSH terms:
Carcinoma, Ductal
Carcinoma, Ductal, Breast
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Ductal, Lobular, and Medullary
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors