Monoclonal Antibody HuHMFG1 in Treating Women With Locally Advanced or Metastatic Breast Cancer

An Open Label Phase I Study of Humanized Human Milk Fat Globule-1 (huHMFG1) Antibody in Patients With Locally Advanced or Metastatic Breast Cancer (TOPCAT)

RATIONALE: Monoclonal antibodies such as HuHMFG1 can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells.

PURPOSE: This phase I trial is studying the side effects and best dose of monoclonal antibody HuHMFG1 in treating women with locally advanced or metastatic breast cancer.

OBJECTIVES:

• Determine the safety and tolerability of monoclonal antibody HuHMFG1 in women with locally advanced or metastatic breast cancer.
• Determine a safe recommended dose and schedule of this drug in these patients.
• Determine the pharmacokinetic profile, in the absence of any other chemotherapy or endocrine agent, of this drug in these patients.
• Determine the antitumor activity of this drug in these patients.
• Determine time to progression in patients treated with this drug.
• Assess immunological markers (e.g., granzyme B, gamma interferon, and C1Q) for determining response to this drug in these patients.
• Assess markers of immunogenicity (e.g., human anti-human antibody) of this drug in these patients.
• Assess tumor markers (e.g., CA15.3 and CEA) in patients treated with this drug.
• Correlate, preliminarily, soluble HMFG1 antigen levels with pharmacokinetic data for this drug in these patients.

OUTLINE: This is an open-label, non-randomized, dose-escalation study.

Patients in cohorts 1 and 2 receive monoclonal antibody HuHMFG1 IV over 1-3 hours once every 21 days for doses 1 and 2. All subsequent dose intervals are based on individual half-life value of the drug, to be within 3 days of the estimated half-life in multiples of 7 days. Patients in cohorts 3 and 4 receive monoclonal antibody HuHMFG1 at the dosing interval determined in the first 2 cohorts. Treatment continues in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of monoclonal antibody HuHMFG1 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

All patients are followed at 4 weeks and then every 6 weeks for 6 months. Patients with an antitumor response or stable disease are followed every 12 weeks until disease progression or initiation of another antitumor treatment.

PROJECTED ACCRUAL: A total of 6-24 patients will be accrued for this study within 18 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed breast cancer

  • Locally advanced or metastatic disease
  • No inflammatory breast cancer

• Measurable (RECIST) or evaluable disease (e.g., cytologically or radiologically detectable disease that does not fulfill RECIST criteria)

• Failed prior OR not a candidate for OR refused anthracycline- and taxane-containing chemotherapy

• Patients whose tumor overexpresses HER-2 must have failed prior trastuzumab (Herceptin®)

• No known CNS metastases

• No metastases accessible to complete surgical resection

• Unstained slides cut from formalin-fixed and paraffin-embedded tumor blocks available

  • Appropriate tumor block also acceptable

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female

Menopausal status

• Not specified

Performance status

• WHO 0-1

Life expectancy

• At least 4 months

Hematopoietic

• Hemoglobin ≥ 10 g/dL
• Absolute neutrophil count ≥ 1,500/mm^3
• WBC ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 mg/dL

• ALT or AST ≤ 2.5 times upper limit of normal (ULN) (< 5 times ULN in patients with liver metastases) OR

• Alkaline phosphatase ≤ 2.5 times ULN (< 5 times ULN in patients with liver metastases)

  • Any degree of elevated alkaline phosphatase allowed provided it is due to bone metastases

Renal

• Creatinine ≤ 1.5 times ULN OR
• Creatinine clearance > 60 mL/min
• Uric acid < 1.25 times ULN (for patients with hyperuricemia only)
• Calcium (corrected for serum albumin) < 11.5 mg/dL (for patients with hypercalcemia only)

Cardiovascular

• LVEF ≥ 45% by MUGA or echocardiogram within the past 4 weeks

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception
• No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer or cervical intra-epithelial neoplasia
• No other uncontrolled illness that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• Prior biological therapy allowed
• More than 2 weeks since prior blood transfusions or growth factors to aid hematological recovery
• No other concurrent antitumor immunotherapy

Chemotherapy

• See Disease Characteristics
• More than 4 weeks since prior cytotoxic chemotherapy
• No more than 3 prior chemotherapy regimens, including adjuvant/neoadjuvant therapy
• No concurrent antitumor chemotherapy

Endocrine therapy

• Prior hormonal therapy allowed
• No concurrent corticosteroids except as physiologic replacement and/or for acute short-term treatment of, or prophylaxis against, infusion reactions
• No concurrent antitumor hormonal therapy

Radiotherapy

• See Disease Characteristics

• More than 4 weeks since prior radiotherapy (except for palliative radiotherapy)

• No concurrent antitumor radiotherapy, except for palliation to non-study lesions

  • Irradiated area should be as small as possible and involve ≤ 10% of the bone marrow in any given 4-week period

Surgery

• More than 4 weeks since prior major surgery

Other

• More than 30 days since prior investigational agents
• No other concurrent investigational agents