A Clinical Trial Evaluating the Safety and Clinical Activity of Radioiodide (131I-) as a Novel Targeted Therapy for Metastatic Breast Cancer That Overexpresses Functional Na/I Symporter

A Phase I/II Clinical Trial Evaluating the Safety and Clinical Activity of Radioiodide (131I-) as a Novel Targeted Therapy for Metastatic Breast Cancer That Overexpresses Functional Na/I Symporter

The purpose of this phase I/II study is to evaluate the safety and clinical activity of Radioiodide (131I-) as a novel targeted therapy for metastatic breast cancer that overexpresses functional Na/I symporter. The study will enroll patients with metastatic breast cancer who have had clinical and/or radiographic evidence of disease progression on prior hormonal and/or chemotherapy.

The primary objectives of the study are as follows:

1. To evaluate the feasibility of using 124I- PET/CT scans to identify patients whose metastatic lesions accumulate radioactive iodide and therefore are candidates for 131I- therapy.
2. Determine the frequency of iodide (124I) enriching metastatic breast cancer.
3. Evaluate the safety and clinical activity of one-time 131I treatment to patients who screen positive on 124I- PET/CT screening, positivity is defined as calculated iodide enrichment that will allow delivering 2000 cGy or more radiation to one or more metastatic lesion by administering up to 200mCi 131I-.

The secondary objectives of the study are as follows:

1. To investigate a correlation between NIS expression in tumor tissue with 124I- uptake on screening PET/CT scan

The Phase I portion will follow a 3+3 design with 4 dose levels (30, 60, 120, and 200 mCi) of I- treatment. The maximum tolerated dose will be used in the Phase II efficacy assessment which will follow a Simon's optimal two-stage design. The primary efficacy measure is objective tumor response rate (CR or PR) with targeted activity level of > 20% response rate.

The study will be terminated for futility if no tumor response is seen in the first 12 patients. If futility criteria is not met, a total of 37 eligible patients will be enrolled in the Phase II portion. If 4 or more responses are seen after 37 patients were evaluated, then the investigators will conclude that the regimen warrants further study.

Inclusion Criteria:

Each patient must meet all inclusion criteria in order to be considered for enrollment:

• Histologically confirmed breast cancer with clinical and/or radiological evidence of measurable or evaluable metastatic disease by Response Evaluation in Solid Tumors (RECIST) 1.1.
• Life expectancy ≥12 weeks.
• Radiologic or clinical evidence of disease progression on prior hormonal and/or chemotherapy
• There is no restriction on the number of prior lines of therapy.
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of < 2.
• Full recovery to Grade ≤ 2 from any prior side effects of prior therapy for cancer including radiation therapy, chemotherapy, and/or immunotherapy.
• Adequate bone marrow function defined as white blood cells (WBCs) ≥ 3.0 × 109/L, neutrophils ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L.
• Adequate renal function defined as serum creatinine < 1.5 mg/dL or creatinine clearance (GFR) > 40 mL/min calculated using the following formula: GFR = 175 x Serum Cr-1.154 x age-0.203 x 0.742 (female) and x 1.212 (if patient is African American).
• Adequate liver function defined as AST, ALT ≤ 3 × upper limit of normal (UNL) in the absence of liver metastasis and ≤ 5 × UNL with liver metastases; bilirubin < 1.5 × UNL; alkaline phosphatase ≤ 2.5 × UNL in the absence of liver metastasis and < 5 × UNL in case of bone metastases.
• TSH, T3 and free T4 must be within normal range.
• The patient should not have had intravenous or intrathecal iodinated contrast agents (IVP, CT with contrast, myelogram, angiogram) for 4 weeks prior to screening to their 124I- PET/CT scans and/or 131I- treatment.
• Patients with treated brain metastases are eligible if the brain metastases have remained stable for more than 4 weeks after completing therapy to the brain.
• Normal urine or serum Beta-HCG in premenopausal women of childbearing potential
• Women of childbearing potential must agree to use effective contraception during the treatment period and for at least 6 months after the last dose of 124I- and/or 131I- as these agents interfere with radioactive iodide uptake
• Signed informed consent.

Exclusion Criteria:

• Concurrent anti-tumor treatment including radiation therapy, hormonal and chemotherapy.
• Patients with symptomatic cardiac disease such as coronary artery disease, congestive heart failure, or atrial fibrillation.
• Significant gastrointestinal abnormalities, including: ulcerative colitis, chronic diarrhea associated with intestinal malabsorption, Crohn's disease, and prior surgical procedures affecting absorption.
• Women who are nursing or pregnant.