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

Phase 1 Clinical Trial of the Combination of Intravenous Alvespimycin (KOS-1022), Trastuzumab With or Without Paclitaxel

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

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Solid Tumor
• Intervention / Treatment: Drug: Alvespimycin; Drug: Trastuzumab; Drug: Paclitaxel

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Melvin & Bren Simon Cancer Center
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Alvespimycin; Solution, IV, 60-100 mg/m2, weekly until disease progression or DLT; Other Names: BMS-826476; Drug: Trastuzumab; Solution, IV, 2-4 mg/kg, weekly until disease progression or DLT; Other Names: Herceptin; BMS-722782
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	Drug: Alvespimycin; Solution, IV, 60-100 mg/m2, weekly until disease progression or DLT; Other Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Dose Limiting Toxicities	During Cycle 1 (4-weeks in duration)

Secondary Outcome Measures

Outcome Measure	Time Frame
Summary of Adverse Events, Serious Adverse Events, Deaths and Discontinuations due to Adverse Events	Weekly
Summary of Clinical Laboratory Abnormalities	Weekly
AUC of KOS-1022 and its metabolites	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
Cmax of KOS-1022 and its metabolites	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
T-Half of KOS-1022 and its metabolites	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
Expression of Hsp90-client proteins in peripheral blood lymphocytes	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
Tumor response as assessed by RECIST criteria first after two cycles of therapy	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)

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (ACTUAL): August 1, 2009
• Study Completion (ACTUAL): August 1, 2009

Study Registration Dates

• First Submitted: December 4, 2008
• First Submitted That Met QC Criteria: December 4, 2008
• First Posted (ESTIMATE): December 5, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): June 27, 2011
• Last Update Submitted That Met QC Criteria: June 23, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Paclitaxel; Trastuzumab
• Other Study ID Numbers: CA201-001; KDG 132