Imetelstat in Combination With Paclitaxel (With or Without Bevacizumab) in Patients With Locally Recurrent or Metastatic Breast Cancer

• Objective response [ Time Frame: Occurring post randomization through end of study period (9 mos. after the last participant is randomized) ] [ Designated as safety issue: No ]
  Objective response as determined by the investigator according to RECIST for patients with measurable disease at baseline.
• Clinical benefit rate [ Time Frame: Occurring post randomization through end of study period (9 mos. after the last participant is randomized) ] [ Designated as safety issue: No ]
  Clinical response rate includes patients with objective response and stable disease lasting at least 6 months.

• Objective response [ Time Frame: Occurring post randomization through end of study period (9 mos. after the last participant is randomized) ] [ Designated as safety issue: No ]
  Objective response as determined by the investigator according to RECIST for patients with measurable disease at baseline.
• Clinical benefit rate [ Time Frame: Occurring post randomization through end of study period (9 mos. after the last participant is randomized) ] [ Designated as safety issue: No ]
  Clinical response rate includes patients with objective response and stable disease lasting at least 6 months.
• The safety and tolerability [ Time Frame: Occurring post randomization through end of study period (9 mos. after the last participant is randomized) ] [ Designated as safety issue: Yes ]
  Safety and tolerability will be assessed by the incidence, nature, and severity of adverse events, laboratory abnormalities, and vital signs.

The purpose of this study is to evaluate the efficacy and safety of treatment with imetelstat + paclitaxel (with or without bevacizumab) versus paclitaxel (with or without bevacizumab) alone for patients with locally recurrent or metastatic breast cancer who have not received chemotherapy or have received one non-taxane based chemotherapy for metastatic breast cancer.

Patients will be randomized in a 1:1 ratio to imetelstat + paclitaxel (with or without bevacizumab) versus paclitaxel (with or without bevacizumab) alone.

• Drug: Imetelstat sodium
  Imetelstat is administered at a dose of 300 mg/m2 on day one of a 21 day cycle.
  Other Name: GRN163L
• Drug: Bevacizumab
  Bevacizumab is administered at 15 mg/kg on day one of a 21 day cycle
  Other Name: Avastin
• Drug: Paclitaxel
  Paclitaxel is administered at 90 mg/m2 on days one and eight of a 21 day cycle
  Other Name: Taxol

• Experimental: Imetelstat + Paclitaxel (with or without bevacizumab)
  Interventions:

  • Drug: Imetelstat sodium
  • Drug: Bevacizumab
  • Drug: Paclitaxel
• Experimental: Paclitaxel (with or without bevacizumab) alone
  Interventions:

  • Drug: Bevacizumab
  • Drug: Paclitaxel

• Hochreiter AE, Xiao H, Goldblatt EM, Gryaznov SM, Miller KD, Badve S, Sledge GW, Herbert BS. Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer. Clin Cancer Res. 2006 May 15;12(10):3184-92.
• Goldblatt EM, Gentry ER, Fox MJ, Gryaznov SM, Shen C, Herbert BS. The telomerase template antagonist GRN163L alters MDA-MB-231 breast cancer cell morphology, inhibits growth, and augments the effects of paclitaxel. Mol Cancer Ther. 2009 Jul;8(7):2027-35. Epub 2009 Jun 9.
• Herbert BS, Wright WE, Shay JW. Telomerase and breast cancer. Breast Cancer Res. 2001;3(3):146-9. Epub 2001 Feb 22. Review.

Inclusion Criteria

• Histologically or cytologically confirmed adenocarcinoma of the breast that is either locally recurrent or metastatic. Locally recurrent disease must not be amenable to surgical resection or radiation with curative intent
• Either have not received chemotherapy or may have had one prior non-taxane chemotherapy regimen for metastatic disease (there are no restrictions on prior hormonal therapy)
• Prior use of bevacizumab is allowed provided that it was not administered in combination with a taxane
• ECOG performance status 0-1

• Adequate bone marrow reserve as indicated by:

  • ANC > 1500/uL (without use of growth factors within 7 days)
  • Platelet count > 100,000 (without transfusion in prior 7 days)
  • Hemoglobin > 9.0 g/dL

Exclusion Criteria:

• Women who are pregnant or breast feeding
• Locally recurrent disease amenable to resection with curative intent
• HER-2-positive breast cancer
• Active central nervous system (CNS) metastatic disease including those patients receiving radiotherapy and/or steroid treatment (within the last 3 months)
• Prior adjuvant or neoadjuvant taxane chemotherapy within 12 months prior of first relapse
• Investigational therapy within 4 weeks of first study drug administration
• Prior radiation, cytotoxic, or hormonal therapy within 2 weeks of first study drug administration
• Therapeutic anti-coagulation or regular use of anti-platelet therapy within 2 weeks prior to first study drug administration (low dose anti-coagulant therapy to maintain patency of a vascular access device is allowed)
• Grade ≥ 2 neuropathy
• Uncontrolled clinically significant atrial or ventricular arrhythmias (unless pacemaker in place)
• Severe conduction disturbance including clinically significant QTC prolongation > 450 ms (unless pacemaker in place)
• Active or chronically recurrent bleeding (e.g., active peptic ulcer disease)
• Clinically relevant active infection
• Known positive serology for human immunodeficiency virus (HIV)