Adenoviral Vector Monotherapy or Combination With Chemotherapy Study in Subjects With Recurrent/Metastatic Breast Cancer and Accessible/Visible Lesions

• Safety and tolerability of study drug therapy based on type and rate of adverse events occurring in the treatment population [ Time Frame: Approximately 24 weeks-Beginning from the time a patient signs the informed consent to the Follow up Tumor Assessment visit ] [ Designated as safety issue: Yes ]
• 16-week PFS rate, calculated as the number of subjects who had not progressed or died prior to 16 weeks from the date of their first dose, divided by the number of subjects in the study arm. [ Time Frame: 16 weeks, starting at the date the first dose of study drug is administered ] [ Designated as safety issue: No ]

• Safety and tolerability of study drug therapy based on type and rate of adverse events occurring in the treatment population [ Time Frame: Approximately 24 weeks-Beginning from the time a patient signs the informed consent to the Post Treatment Safety Visit ] [ Designated as safety issue: Yes ]
• 12-week PFS rate, calculated as the number of subjects who had not progressed or died prior to 12 weeks from the date of their first dose, divided by the number of subjects in the study arm. [ Time Frame: 12 weeks, starting at the date the first dose of study drug is administered ] [ Designated as safety issue: No ]

• Objective response rate (ORR) by modified RECIST v1.1 [ Time Frame: Approximately 24 weeks- From first study drug dose to Follow-Up Tumor Assessment Visit ] [ Designated as safety issue: No ]
  Proportion of subjects achieving a confirmed PR or CR according to modified RECIST v1.1
• Clinical Benefit rate: proportion of subjects with CR, PR, or SD by modified RECIST v1.1 [ Time Frame: Approximately 24 weeks ] [ Designated as safety issue: No ]
• Estimate PFS by modified RECIST v1.1 [ Time Frame: Approximately 24 weeks, beginning at the first study drug administratrion and ending at the Follow up Tumor Assessment visit ] [ Designated as safety issue: No ]
• Evaluate Pharmacodynamic tumor markers in tumor tissue samples that may correlate with objective tumor response and/or clinical outcome [ Time Frame: Approximately 24 weeks, starting with first study drug administrationa and ending at the Follow up Tumor Assessment visit ] [ Designated as safety issue: No ]

• Objective response rate (ORR) by RECIST v1.1 and/or immune related response criteria (irRC): [ Time Frame: Approximately 24 weeks- From first study drug dose to Follow-Up Tumor Assessment Visit ] [ Designated as safety issue: No ]
  Proportion of subjects achieving a confirmed PR or CR according to RECIST v1.1 or irRC during study.
• Clinical Benefit rate: proportion of subjects with CR, PR, or SD by RECIST v1.1 and/or irRC [ Time Frame: Approximately 24 weeks ] [ Designated as safety issue: No ]

Phase II, randomized, safety and efficacy study in recurrent/metastatic breast cancer with accessible lesions.

Primary End point is rate of Progression Free Survival (PFS) at the 16 week treatment time point. Hypothesis: Adenoviral vector (Ad-RTS-hIL-12) alone and in combination with chemotherapy (palifosfamide-tris) is safe and efficacious.

2 Part study:

• Part One: Safety run-in for Ad-RTS-hIL-12 alone arm (A) and palifosfamide-tris alone arm (B). This is followed by a combination therapy (Ad-RTS-hIL-12 + palifosfamide-tris) safety run-in arm (C).
• Part Two: Efficacy evaluation of study treatment arms (A) and (C).

• Genetic: Ad-RTS-hIL-12
  Oral activator ligand with adenoviral vector injection of cancer lesions
• Drug: Palifosfamide-tris
  Small molecule chemotherapy, IV administration

• Experimental: Ad-RTS-hIL-12
  Experimental study drug monotherapy arm (A), Part 1 and 2 of protocol
  Intervention: Genetic: Ad-RTS-hIL-12
• Experimental: Palifosfamide-tris
  Study drug monotherapy arm (B), Part 1 of protocol
  Intervention: Drug: Palifosfamide-tris
• Experimental: Ad-RTS-hIL-12 and palifosfamide-tris
  Study drug combination arm (C), in Part 1 and Part 2 of protocol
  Interventions:

  • Genetic: Ad-RTS-hIL-12
  • Drug: Palifosfamide-tris

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