ErbB2 Over-expressing Metastatic Breast Cancer Study Using Paclitaxel, Trastuzumab, and Lapatinib

A Randomized, Double Blind, Placebo-Controlled, Multicenter, Phase III Study Comparing the Activity of Paclitaxel Plus Trastuzumab Plus Lapatinib to Paclitaxel Plus Trastuzumab Plus Placebo in Women With ErbB2 Overexpressing Metastatic Breast Cancer

This study was originally designed as a Phase III randomized, double blind, placebo controlled study to assess the safety and tolerability, and efficacy of paclitaxel plus trastuzumab plus lapatinib compared with paclitaxel plus trastuzumab plus placebo in women with ErbB2 overexpressing metastatic breast cancer. The planned study was a two stage design with an initial open-label safety stage to be conducted in approximately 65 subjects followed by a randomized phase conducted in a further 700 subjects. The open-label part of the study sequentially enrolled three cohorts with patients receiving a different dose combination of paclitaxel, trastuzumab and lapatinib. Following poor recruitment rate in the open label stage, the randomized stage of the study was terminated, thus no subjects were enrolled into the randomization stage.

The primary objective of this study was to evaluate and compare time to progression (TTP). The Primary objective for open label phase was to determine the safety and tolerability of lapatinib when administered in combination with both paclitaxel and trastuzumab. The study first enrolled an open label safety cohort of 20 patients to assess the tolerability of the triplet combination. This was a 1 arm, 3 cohort study stage.

Open-label Phase: Patients were sequentially enrolled into three cohorts and received an open-label combination of paclitaxel, trastuzumab and lapatinib: Cohort 1 received paclitaxel 80mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 1000 mg PO daily. Cohort 2 received paclitaxel 70mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 1000 mg PO daily. Cohort 3 paclitaxel 80mg/m2 IV weekly for 3 weeks of a 4 week cycle, trastuzumab 4 mg/kg IV loading dose and 2 mg/kg IV weekly, and lapatinib 750 mg PO daily.

Randomized Phase: was terminated following the poor recruitment rate in the open-label safety stage. No subjects were enrolled into the randomization stage.

In summary, at approximately 3.5 years the primary analysis which included demographics, efficacy and safety were conducted; at approximately 7 years protocol amendment 7 cancelled collection of efficacy endpoints, and only key safety endpoints were to be collected; the final analysis was performed at approximately 14 years.

Inclusion criteria:

• Histologically confirmed invasive breast cancer with stage IV disease
• If trastuzumab was administered in the adjuvant setting, >12 months must have elapsed since discontinuation of trastuzumab therapy
• If a taxane was administered in the neoadjuvant or adjuvant setting, progression must have occurred ≥12 months after completion of this treatment
• Had tumors that overexpress ErbB2 defined as either: 3+ by IHC OR c-erbB2 gene amplification by FISH OR 0, 1+, 2+ by IHC and c-erbB2 gene amplification by FISH.
• Patients must have tumor tissue available for central testing, and must have Measurable lesion(s) according to RECIST
• Subjects must be females of at least 18 years Non-childbearing potential or Childbearing potential but using adequate contraception
• Radiotherapy to a limited area other than the sole site of measurable and assessable disease is allowed; however, patients must have completed treatment and recovered from all acute treatment-related toxicities prior to administration of the first dose of study medication
• Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of randomized therapy. Prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1
• For those patients whose disease is estrogen receptor positive+ and/or progesterone receptor + one the following criteria should be met: Patients with visceral disease that requires chemotherapy (eg., patients with liver or lung metastases) or Rapidly progressing/life threatening disease, as determined by the investigator or Patients who received hormonal therapy and are no longer benefiting from this therapy;
• Able to swallow and retain oral medication
• Cardiac ejection fraction within institutional range of normal
• Patient must have adequate organ function

Exclusion criteria:

• Pregnant or lactating females;
• Received prior chemotherapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for metastatic disease, prior hormonal therapy is permitted but must be discontinued a minimum of 7 days prior to randomization;
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Patients with ulcerative colitis are also excluded;
• History of other malignancy; however, patients who have been disease-free for five years, or patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible;
• Concurrent disease or condition that would make the patient inappropriate for study participation, or any serious medical disorder that would interfere with the patient's safety;
• Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment;
• Peripheral neuropathy of Grade 2 or greater;
• Active or uncontrolled infection;
• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;
• Known history of uncontrolled or symptomatic angina, arrhythmias, conduction abnormalities or congestive heart failure;
• Known history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis;
• Concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy);
• Concurrent treatment with an investigational agent or participation in another clinical trial;
• Concurrent treatment with any medication on the prohibited medications list.
• Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of treatment. Hormonal therapy needs to be discontinued at least 7 days before the first dose of treatment.
• Prior therapy with an ErbB2 inhibitor, other than trastuzumab in the adjuvant setting;
• A known immediate or delayed hypersensitivity reaction to drugs chemically related to lapatinib or excipients;
• A known immediate or delayed hypersensitivity reaction to drugs chemically related to paclitaxel or excipients;
• A known immediate or delayed hypersensitivity reaction to drugs chemically related to trastuzumab or excipients;
• Non compliance with any of the screening procedures