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

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.

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.

Eligibility Criteria:
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