A Study Inhibiting Telomerase to Reverse Trastuzumab Resistance in HER2+ Breast Cancer

Inclusion criteria

• Males or females 18 years or older at the time of consent.
• ECOG performance status of 0-2 within 21 days of study registration.
• Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease. NOTE: locally recurrent disease must not be amenable to surgery or radiation with curative intent.
• Measurable or evaluable disease according to RECIST v1.1 within 35 days prior to study registration.
• Disease must be amenable to biopsy (image-guided or via direct visualization of superficial lesions) with minimal risk to the patient. NOTE: Patients with disease limited to the lung and/or pleura are excluded.
• Disease must be HER2+ as defined by IHC 3+ or FISH ratio > 2.0.
• Resistant to trastuzumab as defined as (1) progression within 12 months of completing adjuvant/neoadjuvant trastuzumab or (2) progression on trastuzumab administered for metastatic disease.
• Prior treatment with lapatinib or investigational HER2 targeted therapies is allowed but not required. There are no limits on the number of regimens or other prior anti-HER2 therapies patients have received.
• LVEF ≥ Lower Limit of Normal based on MUGA or ECHO within 35 days prior to study registration
• Females of childbearing potential and males must be willing to use an effective method of contraception from the time consent is signed until 6 months after treatment discontinuation. Methods of contraception include hormonal birth control (oral contraceptives, patch, injection, vaginal ring or implant), two barrier methods of birth control, abstinence and/or other methods as determined by the treating physician.
• Females of childbearing potential must have a negative pregnancy test within 14 days prior to registration for protocol therapy.

NOTE: Females are considered of child bearing potential unless they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal (> 12 months since last menses).

Laboratory values must be obtained within 21 days of study registration:

• Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
• Platelets ≥ 100 K/mm3
• Hemoglobin (Hgb) ≥ 9.0 g/dL (may be transfused)
• Serum creatinine < 3.0 mg/dL
• Total Bilirubin ≤ 1.5 x ULN
• AST/SGOT ≤ 2.5 x ULN. If liver metastases is present, AST ≤ 5 x ULN
• ALT, SGPT ≤ 2.5 x ULN. If liver metastases is present, ALT ≤ 5 x ULN

Exclusion criteria

• No Investigational therapy within 4 weeks of study registration
• No hormonal therapy within 2 weeks of study registration
• No cytotoxic chemotherapy within 2 weeks of study registration.
• No prior treatment with GRN163L
• No prior history of severe reaction to trastuzumab, as determined by the treating physician.
• No history of clinically significant cardiac dysfunction, including:

Current uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg), or unstable angina History of symptomatic CHF (Grade >3 by NCI CTCAE or Class >II by NYHA criteria [see Appendix IV]) or serious cardiac arrhythmia requiring treatment within 12 months of study registration, with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia History of myocardial infarction within 6 months of study registration

• No history of cerebrovascular accident within 12 months of study registration
• No active CNS metastases. Patients with previously treated CNS metastases who do not require chronic steroids or anticonvulsants are eligible.
• Prior radiation therapy must not have involved > 25% of bone marrow due to potential myelosuppression with GRN163L. See bone marrow chart in Appendix III

NOTE: Radiation therapy within 2 weeks of study registration is not allowed.

• Females must not be breastfeeding.
• No clinically significant active infection, as determined by the treating physician