Phase II Lapatinib Plus Nab-Paclitaxel As First And Second Line Therapy In her2+ MBC

Inclusion Criteria:

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

• Subjects must have histologically confirmed invasive breast cancer with Stage IV disease at primary diagnosis or at relapse after curative-intent surgery. Where the disease is restricted to a solitary lesion, the neoplastic nature of the lesion should be confirmed by cytology or histology.
• Documented amplification of ErbB2 3+ by immunohistochemistry or a positive score (>2.2) by FISH using a local laboratory result (which will be considered sufficient in this study with no further verification by a central laboratory).
• Subjects must have received no more than one prior chemotherapeutic regimen in the metastatic setting.
• If a taxane had been administered in the neoadjuvant, adjuvant or metastatic setting, progression must have occurred ≥12 months after completion of this treatment.
• Prior therapy with radiation for this breast cancer population is permitted if it was administered in the neoadjuvant or adjuvant non metastatic setting. Radiotherapy given in the metastatic setting, prior to initiation of study medication, is allowed to a limited area (e.g., palliative therapy and involving less than 25% of bone marrow), if it is not the sole site of disease. Subjects must have completed radiation treatment and recovered from all acute radiation treatment related toxicities (e.g., bone marrow suppression) prior to commencement of combination treatment.
• The subject must have received all prior chemotherapy treatment at least 4 weeks prior to enrollment in this study and must have recovered from all related toxicities. Subjects who have received weekly dose of prior chemotherapy e.g. gemcitabine or capecitabine may enroll 2 to 3 weeks after cessation of treatment provided that they have recovered from all related toxicities.
• Prior therapy with trastuzumab in the neoadjuvant, adjuvant or metastatic setting is permitted. The subject must have received all prior trastuzumab treatment at least 4 weeks prior to enrollment in this study and must have recovered from all related toxicities.
• Prior endocrine therapy is permitted in the neoadjuvant or adjuvant or metastatic setting. The subject must have received all prior endocrine treatment at least 1 week prior to enrollment in this study and must have recovered from all related toxicities.
• Prior diagnosis of cancer is allowed as long as the subject is free of disease for 5 years. Subjects with completely resected basal or squamous cell skin cancer, thyroid cancer or successfully treated cervical carcinoma in-situ will be allowed if it has been 1 year or greater since definitive surgery.
• Subjects must have measurable disease, according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines; defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter [LD] to be recorded) by mammogram, ultrasound or physical exam [Therasse, 2000].
• Subjects with liver metastases or stable chronic liver disease are permitted into the study.
• Women ≥18 years of age:
• Non-child-bearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are postmenopausal); or
• Child-bearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility). This category includes women with oligomenorrhoea (severe), women who are perimenopausal and young women who have begun to menstruate. These subjects must provide a negative serum pregnancy test at Screening and agree to 1 of the following:
• Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 5 days after the final dose of study medication; or
• Consistent and correct use of 1 of the following acceptable methods of birth control:
• Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject.
• Implants of levonorgestrel.
• Injectable progestogen.
• Any intrauterine device with a documented failure rate of less than 1% per year.
• Oral contraceptives (either combined or progestogen only).
• Barrier methods, including diaphragm or condom with a spermicide.
• Considered by the Investigator to have a life expectancy of ≥6 months.
• ECOG Performance Status (PS) of 0 or 1 (Karnofsky ≥80%) [Oken, 1982].
• Subjects must have normal organ and marrow function as defined in Table 3:

CONFIDENTIAL UM2007/00382/01 LPT111111 28

• Table 3 Baseline Laboratory Values for Adequate Organ Function
• Hematologic
• Absolute neutrophil count ≥1.5 × 10^9/L
• Hemoglobin ≥9 g/dL
• Platelets ≥100 × 10^9/L
• Hepatic
• Serum bilirubin ≤ upper limit of normal (ULN)
• Aspartate aminotransferase and alanine aminotransferase
• ≤3 × ULN without liver metastases
• ≤5 × ULN if documented liver metastases
• Renal
• Serum creatinine ≤1.5 mg/dL
• OR -
• Calculated creatinine clearance ≥40 mL/min
• Subjects must have a cardiac ejection fraction of >50% as measured by echocardiogram (ECHO) or multigated acquisition scan (MUGA) and within the institutional range of normal.
• Subjects with stable central nervous system metastases (stable for at least 3 months) as confirmed by computerized tomography (CT)/magnetic resonance imaging (MRI) or evidence of leptomeningeal involvement are eligible only if they are not taking steroids or enzyme-inducing anticonvulsants.
• Subject must be free of gastrointestinal diseases that impede swallowing and retaining of oral medications.
• Signed, informed consent prior to registration.
• Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of study medication. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, is not permitted.
• Subjects whose disease is estrogen receptor + and/or progesterone receptor + or unknown status will only be included in the study if they meet the following criteria:
• They have symptomatic visceral disease that requires chemotherapy.
• Significant visceral organ tumor burden
• The disease is considered by the Investigator to be progressing rapidly or is life threatening.
• Subjects who have received prior endocrine therapy and who are no longer benefiting from this therapy.

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

• Subjects who have received more than one prior chemotherapeutic regimen in the metastatic setting
• Subjects taking treatment with medications provided in the list of restricted medications and substances in the drug information section for lapatinib are not eligible for the study (Section 5.11.2). This includes human immunodeficiency virus-positive subjects receiving combination anti-retroviral therapy because of possible pharmacokinetic interactions with lapatinib.
• Prior treatment with lapatinib.
• Concurrent anticancer or concomitant radiotherapy treatment;
• Concurrent treatment with prohibited medications (Section 5.11.2);
• Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of investigational treatment, or, concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents.
• Known history of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib or nab-paclitaxel or excipients;
• Known history of uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety.
• Pregnant or lactating females at any time during the study (due to the potential teratogenic or abortifacient effects of lapatinib and breastfeeding).
• Subjects with diseases affecting gastrointestinal function resulting in an inability to take oral medication, including; malabsorption syndrome, a requirement for iv alimentation, prior surgical procedures affecting absorption e.g. gastric resection and uncontrolled inflammatory bowel disease (e.g., Crohn's, ulcerative colitis).
• Peripheral neuropathy of Grade 2 or greater.
• Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment.
• History of prior malignancy. However, subjects who have been disease-free for 5 years, or subjects with completely resected basal or squamous cell skin cancer, thyroid cancer or successfully treated cervical carcinoma in situ will be eligible if it has been at least 1 year since definitive surgery.
• or rendering of informed consent.

Other Eligibility Criteria Considerations:

• To assess any potential impact on subject eligibility with regard to safety, the Investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, AEs, and other significant data pertaining to the investigational product(s) being used in this study: Clinical Investigator's Brochure (IB), SPM, and the nab-paclitaxel Product Label.