A Phase II Randomized, Open Label Study of Ad-RTS-hIL-12 Monotherapy or Combination With Palifosfamide-Tris in Subjects With Recurrent/Metastatic Breast Cancer and Accessible Lesions

Inclusion Criteria:

- To be enrolled in the trial, each subject must satisfy all of the following inclusion
criteria:

1. Males or females of all races ≥ 18 years of age, who have provided written
informed consent prior to completing any study specific procedure.

2. Histologically or cytologically confirmed adenocarcinoma of the breast, either
locally recurrent or metastatic disease with injectable lesions, for which no
proven effective therapy exists. Locally recurrent disease must not be amenable
to surgical resection or radiation with curative intent.

3. Subject has failed or progressed on at least 1 prior systemic chemotherapy
regimen ± biologic/experimental therapy (if first-line therapy, failure or
progression during or within the first 30 days).

4. Resolution of all chemotherapy or radiation-related toxicities to Grade 1
severity or lower, except for stable sensory neuropathy ≤ Grade 2 and alopecia.

5. A minimum of 2 lesion(s) assessed by imaging using modified RECIST v1.1, 1 NOT
to be injected AND at least 1 injectable lesion(s)(may use
radiographically-guided injection of lesions if available at site)

6. ECOG performance status 0, 1, 2

7. Male and female subjects must agree to use a highly reliable method of birth
control (expected failure rate less than 5% per year) from the screening visit
through 28 days after the last dose of study drug. Women of childbearing
potential (perimenopausal women must be amenorrheic for at least 12 months to be
considered of non-childbearing potential) must have a negative pregnancy test at
screening.

8. Adequate bone marrow reserve as indicated by:

1. ANC > 1500/μL (without use of growth factors within 7 days)

2. ALC > 700/μL (without use of growth factors within 7 days)

3. Platelet count > 100,000/mm3 (without transfusion in prior 7 days)

4. Hemoglobin > 9.0 g/dL (without transfusion in prior 7 days)

9. Adequate renal function as evidenced by estimated glomerular filtration rate
(eGFR) using the Modification of Diet in Renal Disease (MDRD) equation: eGFR ≥
60 mL/min/1.73 m2

10. Adequate liver function as evidenced by the following:

1. Bilirubin ≤ 1.5 times the upper limits of normal (ULN)

2. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤
2.5×ULN, in the case of liver metastases ≤ 5×ULN

Exclusion Criteria:

- Subjects will be excluded from enrolling in the trial if they meet any of the
following exclusion criteria:

1. Subjects with HER2/neu-positive immunohistochemistry 3+ or fluorescence in situ
hybridization-amplified breast tumors who are eligible for, but who have not
received HER2-targeted therapy (eg, trastuzumab)

2. Concomitant anti-cancer therapies (eg, endocrine therapy for breast cancer)

3. Prior therapies discontinuation periods:

1. Radiation within 3 weeks of enrollment

2. Chemotherapy within 4 weeks of enrollment

3. Nitrosoureas within 6 weeks of enrollment

4. Biologic therapy and/or immunomodulatory therapy (eg, G-CSF/GM-CSF,
interferons or interleukins, growth hormone, IVIG, retinoic acid) within 6
weeks of enrollment

5. Prior therapy with immune checkpoint inhibitors (eg, anti-CTLA4 antibodies,
anti-PD1 antibodies) within 12 weeks of enrollment

6. No washout period is required for endocrine therapy

4. Radiation therapy encompassing >25% of bone marrow

5. History of bone marrow or stem cell transplantation

6. Any congenital or acquired condition leading to an inability to generate an
immune response, including concomitant immunosuppressive therapy

7. Immunosuppressive therapy:

1. Systemic immunosuppressive drugs including corticosteroids (prednisone
equivalent >10 mg/day http://www.medcalc.com/steroid.html) within 8 weeks

2. Immune suppression/requiring immunosuppressive drugs including subjects
with organ allografts requiring any immunosuppression

3. Active autoimmune disease requiring the equivalent of >10 mg/day of
prednisone

8. Major surgery within 4 weeks of study treatment, or major surgery planned for
duration of study participation

9. History of prior malignancy, unless the prior malignancy was diagnosed and
definitively treated ≥5 years previously with no subsequent evidence of
recurrence NOTE: This does not apply to previous breast cancer, carcinoma in
situ of the cervix, inactive melanoma or non-melanoma skin cancer, or Grade 1
papillary bladder cancer

10. Subjects with brain or subdural metastases are not eligible, unless local
therapy completed and corticosteroids discontinued for this indication for ≥4
weeks before starting study treatment. Any signs (eg, radiologic) and/or
symptoms of brain metastases must be stable for ≥4 weeks before starting study
treatment; radiographic stability should be determined by comparing a
contrast-enhanced computed tomography or magnetic resonance imaging brain scan
performed during screening to a prior scan performed at least 4 weeks earlier.

NOTE: Screening for brain lesions by CT or MRI is not required for all potential
subjects; however, if there are any neurological signs or symptoms consistent
with brain metastases, then a brain CT or MRI should be performed as clinically
indicated.

11. Any medications that induce, inhibit or are substrates of CYP450 3A4 within 7
days prior to the first dose of study drug

12. Subjects with meningeal carcinomatosis

13. Known significant hypersensitivity to study drugs or excipients

14. History of malabsorption syndrome or other condition that would interfere with
enteral absorption

15. International Normalized Ratio (INR) and activated partial thromboplastin time
[PTT] <1.5 x ULN, if not therapeutically anticoagulated. Subjects who are being
therapeutically anticoagulated with an agent such as Coumadin (warfarin sodium)
or subcutaneous heparin may be included provided there is no prior evidence of
underlying abnormality in coagulation parameters, screening test results are in
appropriate therapeutic range, and anticoagulation regimen is stable and closely
monitored

16. New York Heart Association (NYHA) Class II or greater congestive heart failure
OR active ventricular arrhythmia requiring medication

17. Any other unstable or clinically significant concurrent medical condition (eg,
infection requiring systemic anti-infective agents) that would, in the opinion
of the investigator, jeopardize the safety of a subject and/or their compliance
with the protocol

18. Localized infection at site of injectable lesion(s)requiring antiinfective
therapy within 2 weeks of the first dose of study drug. NOTE: Appropriate
confirmatory testing (eg, punch biopsy with bacterial counts)must be performed
to rule out the presence of infection if ambiguous, or clinical signs of
infection are evident