Phase I/II Study of Neoadjuvant Lapatinib in Breast Cancer

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of neoadjuvant therapy comprising docetaxel and lapatinib ditosylate before or after fluorouracil, epirubicin hydrochloride, and cyclophosphamide (FEC chemotherapy) in patients with HER2-positive locally advanced, inflammatory, or large resectable breast cancer. (Phase I)
• Determine the safety of this regimen in these patients. (Phase I)
• Determine the pathological complete response rate in patients treated with neoadjuvant docetaxel and lapatinib ditosylate followed by FEC chemotherapy, and with neoadjuvant docetaxel and trastuzumab (Herceptin®) followed by FEC chemotherapy. (Phase II)

Secondary

• Determine the biological activity (i.e., changes in apoptosis and proliferation markers [PTEN mutation and function, pAkt, mTOR, and associated proteins]) of neoadjuvant docetaxel and lapatinib ditosylate in these patients. (Phase I)
• Determine adverse events or biological modifications. (Phase I)
• Determine the tolerability of these regimens in these patients. (Phase II)
• Determine the clinical activity of these regimens. (Phase II)
• Identify genes that may predict response in patients treated with docetaxel and lapatinib ditosylate. (Phase II)

OUTLINE: This is a multicenter, open-label, phase I dose-escalation study of docetaxel and lapatinib ditosylate followed by a randomized phase II study. Patients enrolled in the phase II portion of the study are stratified by institution and disease status (locally advanced disease vs large operable tumor).

• Phase I (completed as of 5/26/2010): Patients receive docetaxel IV over 1 hour on day 1 and oral lapatinib ditosylate once daily on days 1-21. Treatment repeats every 3 weeks for 4 courses. Two additional courses may be given at the discretion of the physician.

• Cohorts of 3-6 patients receive escalating doses of docetaxel and lapatinib ditosylate until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT).
• Phase I bridge step (completed as of 5/26/2010): Patients receive FEC chemotherapy comprising fluorouracil IV over 15 minutes, epirubicin hydrochloride IV over 60 minutes, and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 3 weeks for 3 courses. Patients also receive docetaxel and lapatinib ditosylate as in phase I at the MTD for up to 3 courses.

• Cohorts of 3-6 patients receive de-escalating doses of docetaxel and lapatinib ditosylate in combination with FEC chemotherapy until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT.
• Phase II: Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive docetaxel and lapatinib ditosylate at the MTD as in the bridge step of phase I followed by FEC chemotherapy.
• Arm II: Patients receive docetaxel IV over 60 minutes and trastuzumab (Herceptin®) IV over 30-90 minutes on days 1, 8, and 15. Patients then receive FEC chemotherapy as in the bridge step of phase I. Treatment with docetaxel and trastuzumab repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.
• Arm III: Patients receive docetaxel IV over 60 minutes, lapatinib ditosylate at the MTD as in the bridge step of phase I, and trastuzumab (Herceptin®) IV over 30-90 minutes on days 1, 8, and 15. Patients then receive FEC chemotherapy as in the bridge step of phase I. Treatment with docetaxel, lapatinib ditosylate, and trastuzumab repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

All patients then undergo surgery to remove the tumor. Patients may then receive trastuzumab every 3 weeks for 1 year.

Blood samples are collected at baseline and periodically during study for pharmacokinetic studies. Patients also undergo tumor biopsies at baseline and periodically during study for laboratory studies. Blood and tissue samples are analyzed by quantitative reverse transcriptase polymerase chain reaction for biomarker profiling (HER1-3, Akt 1-3, mTOR, RICTOR, RAPTOR, CCND1, p21, survivin, PTEN), immunohistochemistry, fluorescent in situ hybridization (TopoII, HER2), and proteomics.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 150 patients will be accrued for the phase II.

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive breast cancer meeting the following criteria:

• Phase I

• Locally advanced or inflammatory disease, or specified subgroup of large operable disease for whom neoadjuvant chemotherapy is appropriate, defined as any 1 of the following:

• Clinical stage T4a-d, any N (inflammatory breast carcinoma: tumor mass, breast enlargement, oedema and warmth of the skin are often present but not mandatory for the diagnosis)
• Any clinical T, N2 or N3 (ipsilateral supraclavicular nodes)
• cT3cN0,1 any estrogen receptor (ER)
• cT2cN1 any ER
• cT2cN0 ER negative
• Presence of bilateral breast cancer is allowed
• No bone, liver, or other extensive metastases

• Minimal lung, skin, or nodal metastases may be allowed at the discretion of the investigator (phase I only)
• Phase II

• Locally advanced or inflammatory breast cancer, defined as any 1 of the following:

• Clinical T4a-d, any N (inflammatory breast carcinoma: tumor mass, breast enlargement, oedema and warmth of the skin are often present but not mandatory for the diagnosis)
• Any clinical T, N2 or N3 (ipsilateral supraclavicular nodes)
• And M0
• Bilateral breast cancer is allowed provided only 1 side is HER2-positive
• Any large resectable T2 or T3 breast cancers, M0
• HER2-positive disease by immunohistochemistry, fluorescent in situ hybridization, and/or chromogenic in situ hybridization
• No CNS involvement
• Two frozen trucuts for every core biopsy indicated by the translational research study
• Hormone receptor status:

• Estrogen receptor- and/or progesterone receptor-positive or negative tumor

PATIENT CHARACTERISTICS:

• Female
• WHO performance status 0-2
• Hemoglobin > 10.0 g/dL
• Absolute neutrophil count > 1,500/mm^3
• Platelet count > 100,000/mm^3
• Bilirubin < 1.5 times upper limit of normal (ULN)
• AST and ALT < 3 times ULN
• Creatinine < 1.5 times ULN
• No other malignancies within the past 3 years except basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix (phase II)
• LVEF normal by MUGA or ECHO
• ECG normal
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception 2 weeks prior to, during, and for 1 month after completion of study treatment
• No current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease not requiring therapy as per investigator assessment)
• No serious cardiac illness or medical condition within the past 6 months including, but not limited to, any of the following:

• History of documented congestive heart failure
• High-risk uncontrolled arrhythmias
• Angina pectoris requiring antianginal medication
• Clinically significant valvular heart disease
• Evidence of transmural infarction on ECG
• Poorly controlled hypertension, defined as systolic blood pressure (BP) > 180 mm Hg or diastolic BP > 100 mm Hg
• Able to swallow and retain oral medication
• Accessible for repeat dosing and follow up
• No concurrent grapefruit juice
• No active or uncontrolled infection
• No other serious illness
• No malabsorption syndrome
• No other medical condition (i.e., history of chronic alcohol abuse, hepatitis, HIV, and/or cirrhosis)
• No psychological, familial, sociological, or geographical condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

• No prior therapy for any cancer, including chemotherapy, radiotherapy, or hormonal therapy for breast cancer (phase I)
• No prior epidermal growth factor receptor- or HER2-targeted therapy or antibody therapy (phase I)
• More than 10 days since prior and no concurrent CYP3A4 inducers or inhibitors
• More than 14 days since prior and no concurrent herbal infusions or dietary supplements
• No antacids 1 hour before or after lapatinib ditosylate administration
• No other concurrent investigational therapy or anticancer therapy
• No concurrent prophylactic antibiotics