Efficacy and Safety of IPI-504 With Trastuzumab Pretreated, Locally Advanced or Metastatic HER2 Positive Breast Cancer

A Phase 2 Multicenter Study Evaluating the Efficacy and Safety of IPI-504 in Combination With Trastuzumab in Patients With Pretreated, Locally Advanced or Metastatic Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer

The purpose of this study is to see if IPI-504 in combination with trastuzamab is an effective treatment in HER2 positive metastatic breast cancer

Recent clinical data has demonstrated that even in heavily pretreated patients with trastuzumab-refractory HER-2 positive breast cancer, targeting HER2 is efficacious.

IPI-504 is an HSP90 inhibitor and is chemically related to 17-AAG and it has been studied in a clinical trial in combination with trastuzamab and a response rate of 26% (7/27) was demonstrated in patients with pretreated, HER2-positive breast cancer. These data provide a strong scientific rationale for clinical testing of IPI-504 plus trastuzumab in patients with pretreated, locally advanced or metastatic HER2-positive breast cancer

Inclusion Criteria:

• Locally advanced/metastatic breast cancer.

• HER2-expressing primary or metastatic tumor

• Two prior regimens with HER2. Trastuzumab must have been given. No limit to prior therapies

• Measurable disease with RECIST 1.1

• Clinical progression

• LVEF WNL

• ECOG 0 or 1

• Last dose of chemotherapy, radiotherapy, surgery, ablative therapy, tyrosine kinase inhibitor, ≥2 weeks

• Administration of biological therapy ≥4 weeks

• Last dose of trastuzumab must be ≥1, or ≥3 weeks prior to start, if previously administered on an every 3 week schedule.

• Resolution of toxic effects to baseline or Grade 1, except alopecia (NCI CTCAE Version 3.0

• Organ and marrow function:

  • Hemoglobin ≥8.0 g/dL
  • ANC ≥1200/µL
  • Platelets ≥75,000 /µL
  • ALT and AST ≤ 1.5 x ULN
  • Alkaline phosphatase ≤2.5 x ULN, or ≤3.0 x ULN if secondary to liver metastases.
  • Serum bilirubin WNL
  • Serum albumin ≥3.0 g/dL
  • PT, PTT ≤1.5 x ULN
  • Serum creatinine ≤1.5 x ULN

• Negative pregnancy test

Exclusion Criteria:

• Prior treatment with Hsp90 inhibitor.
• Grade 4 AE secondary to trastuzumab. Grade 3/4 infusion reactions or Grade 3/4 symptomatic heart failure
• Medication/food that is a CYP3A inhibitor or inducer.
• Hx 6 months: cardiac disease - acute coronary syndrome or unstable angina, symptomatic congestive heart failure, uncontrolled hypertension, cirrhotic liver disease, cerebrovascular accident or significant co-morbid condition
• Grade 3 or 4 hemorrhagic event within 6 months.
• HIV positivity
• Baseline QT corrected, QTcF >470 ms
• Sinus bradycardia <50 bpm Secondary to pharmacologic therapy may enroll if stopping therapy normalizes heart rate.
• Malignancies within 3 years other than non-melanomatous skin cancers, non-muscle-invasive bladder cancer and carcinoma in situ of cervix.
• Active keratitis or keratoconjunctivitis
• Active brain metastasis (e.g., requiring therapy with steroids or radiation therapy; or with intracranial progression 4 weeks after the completion of radiation therapy) uncontrolled seizure disorder, ongoing spinal cord compression, or carcinomatous meningitis. If clinically stable brain metastasis (previously treated or untreated)are present pt is eligible.