Safety Study of AMG 386 to Treat HER2-positive Locally Recurrent or Metastatic Breast Cancer

• To evaluate the incidence of adverse events and clinical laboratory abnormalities not defined as DLTs [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
• To evaluate the pharmacokinetics (PK) of AMG 386, trastuzumab, and paclitaxel (cohort A) or AMG 386, lapatinib, and capecitabine (and its active metabolite, 5-FU; cohort B) when administered in combination [ Time Frame: 24 months ] [ Designated as safety issue: No ]
• To estimate the incidence of anti AMG 386 antibody formation [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
• To evaluate the treatment effect as measured by the following: objective response rate (ORR), duration of response (DOR), change in tumor burden and progression-free survival (PFS) [ Time Frame: 23 months ] [ Designated as safety issue: No ]

The purpose of this study is to determine if AMG 386 in combination with either paclitaxel and trastuzumab or capecitabine and lapatinib is safe and well tolerated in subjects with HER2-positive locally recurrent or metastatic breast cancer.

This is an open-label phase 1b trial and has 2 study parts. Study part 1 is a dose escalation study to determine a tolerable dose of AMG 386 in combination with paclitaxel and trastuzumab (cohort A) or with capecitabine and lapatinib (cohort B). Study part 2 is cohort expansion of the tolerable doses determined in part 1.

• Breast Cancer
• Breast Neoplasms
• Breast Tumors
• Cancer
• Locally Recurrent and Metastatic Breast Cancer
• Metastases
• Metastatic Cancer
• Oncology
• Solid Tumors
• Tumors

• Drug: AMG 386 15 mg/kg, Capecitabine and Lapatinib
  AMG 386 15 mg/kg IV QW, capecitabine 2000 mg/m2 divided into 2 doses given PO Q12 hrs, days 1-14 every 21 days, lapatinib 1250 mg PO QD
• Drug: AMG 386 15mg/kg, Paclitaxel and Trastuzumab
  AMG 386 15 mg/kg IV QW, paclitaxel 80 mg/m2 IV QW, trastuzumab: initial dose 8 mg/kg IV week 1, then 6 mg/kg IV Q3W
• Drug: AMG 386 30 mg/kg, Paclitaxel and Trastuzumab
  AMG 386 30 mg/kg IV QW, paclitaxel 80 mg/m2 IV QW, trastuzumab: initial dose 8 mg/kg IV week 1, then 6 mg/kg IV Q3W
• Drug: AMG 386 30 mg/kg, Capecitabine and Lapatinib
  AMG 386 30 mg/kg IV QW, capecitabine 2000 mg/m2 divided into 2 doses given PO Q12 hrs, days 1-14 every 21 days, lapatinib 1250 mg PO QD
• Drug: AMG 386 10 mgkg, Paclitaxel and Trastuzumab
  AMG 386 10 mg/kg IV QW, paclitaxel 80 mg/m2 IV QW, trastuzumab: initial dose 8 mg/kg IV week 1, then 6 mg/kg IV Q3W
• Drug: AMG 386 10 mg/kg, Capecitabine and Lapatinib
  AMG 386 10 mg/kg IV QW, capecitabine 2000 mg/m2 divided into 2 doses given PO Q12 hrs, days 1-14 every 21 days, lapatinib 1250 mg PO QD

• Experimental: Cohort A1
  Intervention: Drug: AMG 386 10 mgkg, Paclitaxel and Trastuzumab
• Experimental: Cohort A3
  Intervention: Drug: AMG 386 30 mg/kg, Paclitaxel and Trastuzumab
• Experimental: Cohort B4
  Intervention: Drug: AMG 386 15 mg/kg, Capecitabine and Lapatinib
• Experimental: Cohort A4
  Intervention: Drug: AMG 386 15mg/kg, Paclitaxel and Trastuzumab
• Experimental: Cohort B1
  Intervention: Drug: AMG 386 10 mg/kg, Capecitabine and Lapatinib
• Experimental: Cohort B3
  Intervention: Drug: AMG 386 30 mg/kg, Capecitabine and Lapatinib

Inclusion Criteria:

• Subjects must have histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease. Locally recurrent disease must not be amenable to any local treatment with curative intent.
• HER2-positive by FISH, CISH, or IHC 3+
• ECOG performance status 0 or 1
• Left ventricular ejection fraction greater than or equal to institutional lower limit of normal
• Adequate laboratory studies (hematological, chemistries and urinalysis)
• Life expectancy greater than or equal to 3 months
• Cohort A only:
• Subjects must be either trastuzumab naïve or have had prior trastuzumab in the neo-adjuvant setting only
• Subjects must not have had a clinically significant drop in cardiac function during a prior exposure to trastuzumab
• Subjects must have had no prior chemotherapy for metastatic or locally recurrent breast cancer
• Subjects must have had no prior lapatinib therapy
• At least 3 weeks from enrollment since prior chemotherapeutic agents, including taxanes, in the neoadjuvant or adjuvant setting
• At least 3 months from enrollment since prior trastuzumab in the neoadjuvant or adjuvant setting
• Cohort B only:
• Subjects must have failed (due to disease progression or toxicity) trastuzumab in the first-line metastatic setting. Trastuzumab must be discontinued for at least 3 weeks prior to enrollment
• Subjects must have received prior chemotherapy as adjuvant therapy or for metastatic disease
• Prior chemotherapy treatment must be discontinued for at least 3 weeks prior to enrollment
• Subjects must have had no prior capecitabine
• Subjects must have had no prior lapatinib

Exclusion Criteria:

• Inflammatory breast cancer
• Current or prior history of central nervous system metastasis
• Clinically significant cardiovascular disease
• Radiation therapy ≤ 14 days prior to enrollment. Subjects must have recovered from all radiation therapy related toxicities.
• Concurrent or prior (within 1 week before enrollment) anticoagulation therapy, excluding aspirin and anti-platelet agents. The concurrent use of low molecular weight heparin or low dose warfarin (ie, less than or equal to 1 mg daily) for prophylaxis against thrombosis is acceptable while on study
• Uncontrolled hypertension defined as diastolic blood pressure > 90 mmHg OR systolic blood pressure > 140 mmHg. The use of anti-hypertensive medications to control hypertension is permitted.
• Subjects with a history of prior malignancy, except:
• Malignancy treated with curative intent and with no known active disease present for greater than or equal to 3 years before enrollment and felt to be at low risk for recurrence by treating physician
• Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease
• Adequately treated cervical carcinoma in situ without evidence of disease
• Subjects with interstitial pulmonary disease
• For Cohort B only:
• Current or prior history of long QT syndrome
• Baseline ECG report of QTc interval of > 480 milliseconds
• Severe chronic liver disease (Child Pugh C)