A Study of Ad-RTS-hIL-12 With Veledimex in Subjects With Breast Cancer

This is a single-arm, phase Ib/II study to examine the safety, tolerability and preliminary efficacy of one cycle of Ad-RTS-hIL-12 immunotherapy in women with advanced breast cancer and pre-study SD or PR after completion of a minimum 12 week course of standard first- or second-line chemotherapy. The patient population will include patients with locally advanced or metastatic breast cancer of all subtypes.

Subjects who have PD or a CR after the standard chemotherapy are not eligible for the study. Following entry into the trial, patients will go on a treatment holiday from chemotherapy and enter an immunotherapy phase of treatment. Continuation of HER2-targeted antibody therapy is permitted during this immunotherapy phase for women with HER2+ disease. Scans will be conducted at 6 and 12 weeks after the start of Ad-RTS-hIL-12 immunotherapy to determine tumor response. Radiographic PD at week 6 must be confirmed at least 4 weeks later, either at week 12 or earlier if clinically necessitated.

Eligibility Criteria:
Inclusion Criteria:

1. Female, age ≥ 18 years
2. Histologically-confirmed, locally advanced or metastatic adenocarcinoma of the breast
3. Achievement of SD or PR after a minimum of 12 weeks of pre-study first- or second-line standard chemotherapy
4. Presence of at least 2 measurable lesions
5. Standard treatment interrupted, except if anti-HER2 therapy
6. All treatment-related or radiation-related toxicities resolved to Grade 1 or lower
7. Submission of copies of tumor measurements and scans
8. Life expectancy \> 12 weeks
9. ECOG performance status of 0 to 1
10. Adequate bone marrow function
11. Adequate liver function
12. Adequate renal function
13. Female subjects and their male partners must agree must agree to use a highly reliable method of birth control
14. Able to swallow oral medication
15. Willing to comply with study procedures

Exclusion Criteria:

1. Metastatic breast cancer patients currently on hormonal therapy as first- or second-line are not permitted
2. Prior radiation therapy encompassing \> 25% of bone marrow
3. Any congenital or acquired condition leading to compromised ability to generate an immune response
4. Immunosuppressive therapy

   1. Use of systemic immunosuppressive drugs
   2. Requirement for continual immune suppression
5. Major surgery within 4 weeks of study treatment
6. An active, second potentially life-threatening cancer
7. Presence of brain or subdural metastases

   1. Any signs and/or symptoms of brain metastases must be stable for ≥ 4 weeks
   2. Radiographic stability should be determined by comparing contrast-enhanced CT or MRI scans at screening to scans obtained by the same method at least 4 weeks earlier
8. Presence or documented history of any of the following autoimmune conditions:

   1. Inflammatory bowel disease
   2. Rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis
   3. Motor neuropathy considered of autoimmune origin
9. Presence of meningeal carcinomatosis
10. Use of any medications that induce, inhibit, or are substrates of CYP450 3A4
11. History or evidence of cardiac disease as indicated by any of the following:

    1. Congestive heart failure greater than NYHA Class II
    2. Unstable angina or new-onset angina (begun within the last 3 months), or myocardial infarction within the 6 months prior to enrollment
    3. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
    4. Congenital long QT syndrome or taking drugs known to prolong the QT interval
12. Current use of any drugs with a known risk of causing torsades de pointes
13. Evidence or history of thromboembolic, venous, or arterial events within the past 3 months
14. Evidence or history of bleeding diathesis or coagulopathy
15. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) \> 1.5 x ULN, in subject who is not therapeutically anticoagulated.
16. History of malabsorption syndrome or other condition that would interfere with enteral absorption
17. Presence of active clinically serious infection
18. Diagnosis of infection with HIV or chronic infection with hepatitis B or C
19. Any other unstable or clinically significant concurrent medical condition
20. Pregnant or breast-feeding
21. Use of any investigational, non-United States Food and Drug Administration (US FDA) approved drug
22. Participation in any other clinical trial
23. Presence of any condition which makes the patient unsuitable