Preoperative Chemotherapy With Paclitaxel, Gemcitabine, and Lapatinib (Tykerb®) (PGT)

Jungsil Ro

Status and phase

Completed

Phase 1

Conditions

Breast Cancer

Treatments

Drug: paclitaxel, gemcitabine, lapatinib

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT01133912

NCCCTS-08-370

Details and patient eligibility

About

Primary objectives :

To evaluate the recommended dose of the combination of paclitaxel, gemcitabine, and lapatinib (Tykerb®) (PGT) as preoperative chemotherapy in patients with HER2 positive operable breast cancer

Secondary objectives :

To evaluate the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of PGT
To determine the safety profile
To assess pCR in primary tumor and axillary LN
To evaluate clinical response rate, disease free survival (DFS), and overall survival (OS)
To assess breast conserving rate after preoperative PGT

Full description

Unlike adjuvant chemotherapy, primary (preoperative) chemotherapy will shrink tumor and allow some patients to become candidates for conservative surgery and avoid mastectomy. It also is an in vivo chemosensitivity test and the result is a predictive marker for clinical outcomes. Paclitaxel is a highly active antitumor agent that promotes microtubule assembly by binding to tubulin and inhibiting depolymerization. Paclitaxel has been shown to be an effective agent in the treatment of breast cancer. Gemcitabine is a cytosine arabinoside prodrug analog and shows response rates of 15% to 46% as a single agent with very low toxicity. The combination of gemcitabine and paclitaxel is valuable because of the different mechanisms of action of each drug and their non-overlapping toxicities. Phase II studies of paclitaxel plus gemcitabine in anthracycline-pretreated metastatic breast cancer showed good tolerance and encouraging response rates (40%-55%). Paclitaxel plus gemcitabine combination showed overall survival benefit compared to paclitaxel alone in patients with metastatic breast cancer in an interim overall survival report. A phase II study with preoperative paclitaxel and gemcitabine in stage II/III showed 18 % pCR rate at NCC (ASCO 2007 abstract #11080) In HER2 positive breast cancer, HER2 targeted therapies with trastuzumab and lapatinib have shown much improved clinical response in palliative setting. It also showed that adding trastuzumab to sequential paclitaxel and FEC chemotherapy significantly increased pCR (25% vs 66.7%) in preoperative setting for HER2 positive disease. Recently, paclitaxel, gemcitabine, and trastuzumab combination (PGH) for 6 cycles in patients with HER2 positive and node positive operable breast cancer observed a strikingly high pCR rate in both tumor and LN in an interim analysis of multicenter phase II preoperative study in Korea (28 of 47 (61%)). Lapatinib (Tykerb®), a dual tyrosine kinase inhibitor of ErbB1 and HER2 signaling pathways and it has shown to inhibit the growth of HER2 overexpressing breast cancer cells that do not respond to trastuzumab after long-term conditioning. We will examine the hypothesis that paclitaxel, gemcitabine, and lapatinib (Tykerb®) (PGT) combination could improve the pathological complete response rate of HER2 positive breast cancer when applied as a preoperative chemotherapy.

Enrollment

13 patients

Sex

Female

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Histologically confirmed and newly diagnosed operable breast cancer
Documented HER2 positive disease : 3+ overexpression by IHC or HER2 gene amplification by FISH
ECOG performance status 0-2
Age ≥ 18 years
Clinical stage II or III operable breast cancer
Axillary node positivity determined by cytology
No prior hormonal, chemotherapy, or radiotherapy is allowed
No breast operation other than biopsy to make diagnosis is allowed
Negative urine pregnancy test within 7 days prior to registration in premenopausal patients
Adequate hematopoietic function: Absolute granulocyte count ≥1,500/mm3, platelet ≥100,000/mm3, hemoglobin ≥10g/mm3
Adequate hepatic function: total bilirubin ≤1.5mg/dL, AST/ALT ≤2 x UNL, alkaline phosphatase ≤2 x UNL
Adequate renal function: Serum creatinine ≤1.5mg/dL
Adequate cardiac function:
1. Normal or nonspecific EKG taken within 1 month of enrollment
2. LVEF ≥50% by MUGA or echocardiogram taken within 4 weeks of enrollment
Ability to understand and comply with protocol during study period
Patients should sign a written informed consent before study entry

Exclusion criteria

Pregnant or lactating women
Patients who received hormonal, chemotherapy or radiotherapy for breast cancer
Patients with bilateral breast cancer
Patients who underwent surgery for breast cancer
Patients with node-negative stage IIA (T2N0) breast cancer
Patients who have history of cancer other than in situ uterine cervix cancer or nonmelanotic skin cancer
Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled GI disease (e.g., Crohn's disease, ulcerative colitis)