Clinical Trial of the Combination of Intravenous Alvespimycin (KOS-1022), Trastuzumab With or Without Paclitaxel in Patients With Advanced Solid Tumor Malignancies or Her2 Positive Metastatic Breast Cancer Who Have Previously Failed Trastuzumab Therapy

• No formal analysis of efficacy will occur. For patients with measurable disease, response will be assessed by RECIST criteria first after two cycles of therapy (8 weeks in patients having no delay in the schedule of administration) [ Time Frame: For patients with measurable disease, response will be assessed by RECIST criteria first after two cycles of therapy ] [ Designated as safety issue: No ]
• Subsequent response evaluations will occur following every two cycles of treatment (8 weeks). All patients with responding tumors (CR or PR) must have the response confirmed 4 weeks after the first documentation of response, confirmed by CT [ Time Frame: Subsequent response evaluations will occur following every two cycles of treatment (8 weeks) ] [ Designated as safety issue: No ]

• Summary of Adverse Events, Serious Adverse Events, Deaths and Discontinuations due to Adverse Events [ Time Frame: Weekly ] [ Designated as safety issue: Yes ]
• Summary of Clinical Laboratory Abnormalities [ Time Frame: Weekly ] [ Designated as safety issue: Yes ]
• AUC of KOS-1022 and its metabolites [ Time Frame: Week 1 and Week 4: pretreatment, 30 and 55 minutes after start of infusion, 5, 15, 30 minutes and 1, 2, 4, 6, 24, 72 hours post-infusion; Weeks 2 and 3: pre-infusion ] [ Designated as safety issue: No ]
• Cmax of KOS-1022 and its metabolites [ Time Frame: Week 1 and Week 4: pretreatment, 30 and 55 minutes after start of infusion, 5, 15, 30 minutes and 1, 2, 4, 6, 24, 72 hours post-infusion; Weeks 2 and 3: pre-infusion ] [ Designated as safety issue: No ]
• T-Half of KOS-1022 and its metabolites [ Time Frame: Week 1 and Week 4: pretreatment, 30 and 55 minutes after start of infusion, 5, 15, 30 minutes and 1, 2, 4, 6, 24, 72 hours post-infusion; Weeks 2 and 3: pre-infusion ] [ Designated as safety issue: No ]
• Expression of Hsp90-client proteins in peripheral blood lymphocytes [ Time Frame: Pretreatment, 4 hours following the Day 1 KOS-1022 infusion, Day 2, Day 4; pretreatment samples Weeks 2 and 3; pretreatment, 4 hours following the Day 22 KOS-1022 infusion, Day 23, Day 25 ] [ Designated as safety issue: No ]
• Tumor response as assessed by RECIST criteria first after two cycles of therapy [ Time Frame: For patients with measurable disease, response will be assessed by RECIST criteria first after two cycles of therapy (8 weeks in patients having no delay in the schedule of administration) ] [ Designated as safety issue: No ]

• To evaluate the safety and cumulative toxicity of repeated dosing of KOS-1022 when administered in combination with trastuzumab or trastuzumab/paclitaxel [ Time Frame: Weekly ] [ Designated as safety issue: Yes ]
• 2. To determine the pharmacokinetics of KOS-1022 when delivered via weekly infusion when administered in combination with trastuzumab or trastuzumab/paclitaxel [ Time Frame: Weekly during Cycle 1 ] [ Designated as safety issue: Yes ]
• To determine the effect of KOS-1022 on the expression of Hsp90-client proteins in peripheral blood lymphocytes [ Time Frame: Pretreatment, 4 hours following the Day 1 KOS-1022 infusion, Day 2, Day 4; pretreatment samples Weeks 2 and 3; pretreatment, 4 hours following the Day 22 KOS-1022 infusion, Day 23, Day 25 ] [ Designated as safety issue: Yes ]
• To describe any evidence of anti-tumor activity [ Time Frame: Every 8 weeks ] [ Designated as safety issue: Yes ]

To determine the Maximally Tolerable Dose (MTD) of KOS-1022 when administered weekly in combination with trastuzumab or in combination with trastuzumab and paclitaxel to patients with advanced solid tumor malignancies

• Solid Tumor
• Breast Cancer

• Drug: Alvespimycin
  Solution, IV, 60-100 mg/m2, weekly until disease progression or DLT
  Other Name: BMS-826476
• Drug: Trastuzumab
  Solution, IV, 2-4 mg/kg, weekly until disease progression or DLT
  Other Names:

  • Herceptin
  • BMS-722782
• Drug: Paclitaxel
  Solution, IV, 60-90 mg/m2, weekly until disease progression or DLT
  Other Names:

  • Taxol
  • BMS-181339

• Experimental: Arm 1

  Patients whose last dose is > 21 days prior to first dose of Trastuzumab on study. First infusion: 90 mins for 4 mg/kg loading dose of trastuzumab followed by 60 min infusion of alvespimycin. Subsequent infusions weekly 30 mins for 2 mg/kg trastuzumab followed by 60 min infusion of alvespimycin

  Patients whose last dose is < 21 days prior to first dose of Trastuzumab on study. All infusions: 30 mins for 2 mg/kg trastuzumab followed by 60 min infusion of alvespimycin

  Interventions:

  • Drug: Alvespimycin
  • Drug: Trastuzumab
• Experimental: Arm 2

  Patients whose last dose is > 21 days prior to first dose of Trastuzumab on study. First infusion: 90 mins for 4 mg/kg loading dose of trastuzumab followed by 60 min infusion of paclitaxel and 60 min of infusion of alvespimycin. Subsequent infusions weekly 30 mins for 2 mg/kg trastuzumab followed by 60 min infusion of paclitaxel and 60 min infusion of alvespimycin

  Patients whose last dose is < 21 days prior to first dose of Trastuzumab on study. All infusions: 30 mins for 2 mg/kg trastuzumab followed by 60 min infusion of paclitaxel and 60 min infusion of alvespimycin. Subsequent infusions weekly 30 mins for 2 mg/kg trastuzumab followed by 60 min infusion of paclitaxel and 60 min infusion of alvespimycin

  Interventions:

  • Drug: Alvespimycin
  • Drug: Trastuzumab
  • Drug: Paclitaxel

Inclusion Criteria:

• KPS performance status >= 70%
• Schedule A: all patients must have a histologically confirmed solid tumor malignancy. Schedule B: patients must have metastatic breast cancer with Her2 amplification by FISH or 3+ Her2 overexpression by immunohistochemistry ("IHC"). Patients are not required to have measurable disease for this investigation. Disease must be assessed within 28 days prior to treatment initiation
• All Adverse Events of any prior chemotherapy, surgery, or radiotherapy, must have resolved to NCI CTCAE (v. 3.0) Grade <= 2 (except for alopecia)

• The following laboratory results, within 10 days of KOS-1022 administration:

  • Hemoglobin >= 8.5 g/dL
  • Absolute neutrophils count >= 1.5 x 10*9* /L
  • Platelet count >= 75 x 10*9*/L
  • Serum bilirubin <= 2 x ULN
  • AST and ALT <= 2.5 x ULN
  • Serum creatinine <= 2 x ULN

Exclusion Criteria:

• Documented hypersensitivity reaction of CTCAE Grade >= 3 to prior therapy containing trastuzumab
• Pregnant or breast-feeding women. Male patients must be surgically sterile or agree to use an acceptable method of contraception
• Known active CNS metastases
• Administration of any other chemotherapy, biological, immunotherapy or investigational agent (therapeutic or diagnostic) within 14 days prior to receipt of study medication. Patients should be 6 weeks from last dose of nitrosourea
• Patients with Grade 2 or higher dyspnea at rest on room air; patients with other clinically significant pulmonary co-morbidity(s) that might predispose the patient to pulmonary toxicity
• Moderately severe dry eye
• Prior pulmonary toxic chemotherapy (e.g, bleomycin or carmustine)
• Congestive heart failure, or a left ventricular ejection fraction (LVEF)
• Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient
• Patients with previous malignancies unless free of recurrence for at least 5 years except cured basal cell carcinoma of the skin, carcinoma-in-situ of either the uterine cervix or urinary bladder