A Phase 1-2, XIAP Antisense AEG35156 With Weekly Paclitaxel in Patients With Advanced Breast Cancer

This is an open-label multicenter, phase 1-2 study. Following determination of the recommended AEG35156 dose in combination with weekly paclitaxel in the initial Phase 1 part of this study, additional patients will be enrolled in the Phase 2 part of the study to assess the activity of the combination in advanced breast cancer.

Breast cancer is the most common cancer in women in the United States, the second most common cause of cancer death, and the main cause of death in women ages 45 to 55. In 2006, 212,920 American women will be diagnosed with breast cancer, and 40,970 will die from this disease.\[1\]. Fewer than 10 percent of women present with metastatic disease at the time of diagnosis. However, the majority of women who relapse after initial definitive therapy for early stage or locally advanced disease will do so with disseminated metastatic disease rather than an isolated local recurrence. Treatment for metastatic disease is palliative in intent and will usually involve hormone therapy and/or chemotherapy with or without trastuzumab. Active chemotherapy agents include anthracyclines, taxanes, vinorelbine, alkylating agents and antimetabolites. Taxanes have become the cornerstone of first-line treatment for metastatic breast cancer. Weekly doses of paclitaxel can be administered continuously for several weeks with a remarkable lack of myelosuppression \[2\]. Weekly paclitaxel (80 mg/m2) was directly compared to every three-week therapy (175 mg/m2) in 585 women with metastatic breast cancer. Weekly therapy was associated with a significantly higher response rate (40 versus 28 percent) and longer TTP (nine versus five months), but similar overall survival and worse neurotoxicity \[3\]. Since patients with metastatic breast cancer are unlikely to be cured of their disease \[4\], they should be considered candidates for a clinical trial.

Eligibility Criteria:
Inclusion Criteria:

* Patients with histologically or cytologically confirmed breast adenocarcinoma who are candidates for paclitaxel single agent chemotherapy for metastatic breast cancer
* ECOG performance \< 2
* One or more metastatic tumors measurable by RECIST criteria on CT scan or MRI (Phase 2 part only)
* Life expectancy of at least 6 months
* Age \> 18 years
* Signed, written IRB-approved informed consent
* A negative serum pregnancy test (if applicable)
* Acceptable liver function:
* Bilirubin within normal limit
* AST (SGOT), ALT (SGPT) and Alkaline phosphatase \< 2.0 times the institution's upper limit of normal
* Acceptable renal function:
* Serum creatinine within normal limits, OR calculated creatinine clearance \> 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
* Acceptable hematologic status:
* Granulocyte \> 1500 cells/uL
* Platelet count \> 100,000 plt/uL
* Hemoglobin \> 9.0 g/dL
* Acceptable coagulation status:
* PT within normal limits
* PTT within normal limits
* For women of child-bearing potential, the use of effective contraceptive methods during the study
* Prior radiotherapy is allowed provided disease progression outside the radiation field has been documented, and treatment completed at least 2 weeks prior to registration

Exclusion Criteria:

* Prior taxane chemotherapy for metastatic disease.
* More than one prior chemotherapy regimen for metastatic disease
* Active progressive brain metastases including the presence of any related symptoms or need for corticosteroids. A CT or MRI scan of the head is necessary in patients with a history of brain metastases to document the stability of prior lesions
* Grade \> 2 peripheral neuropathy
* Known bleeding diathesis or concurrent treatment with anticoagulants except patients on non-therapeutic line maintenance coumadin
* Pregnant or nursing women. NOTE: Women of child-bearing potential must agree to use adequate contraception (sterile or surgically sterile; hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
* Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
* Known infection with HIV, hepatitis B, or hepatitis C
* Serious nonmalignant disease that could compromise protocol objectives in the opinion of the investigator and/or the sponsor
* Patients who are currently receiving any other investigational agent. Subjects who have used a previous antisense oligonucleotide in the last 90 days will be excluded
* Unwillingness or inability to comply with procedures required in this protocol
* Any deviation from these inclusion/exclusion criteria must be discussed with the sponsor prior to enrolling patient.