Clinical trial NCT01133912: Preoperative Chemotherapy With Paclitaxel, Gemcitabine, and Lapatinib (Tykerb®) (PGT)
Official title: Phase Ib Study of Preoperative Chemotherapy With Paclitaxel, Gemcitabine, and Lapatinib (Tykerb®) (PGT) in Patients With HER2 Positive Operable Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Keywords: Patients with HER2 Positive Operable Breast Cancer
Lead sponsor: National Cancer Center, Korea
Sponsor class: OTHER_GOV
Collaborators: name: GlaxoSmithKline
name: HK inno.N Corporation
First posted: 2010-05-31
Enrollment: 13
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Primary objectives :

1. 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 :

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

Detailed 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.

Eligibility criteria: 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)

Primary outcomes:
measure: 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
timeFrame: two years
Secondary outcomes:
Other outcomes:
Locations:
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
state: Gyeonggi-do
Study officials:
affiliation: National Cencer Center, Korea
name: Jungsil Ro, MD
role: PRINCIPAL_INVESTIGATOR
References: