A Phase 2, Multi-Cohort, Open-Label Study of Intratumoral Tavokinogene Telseplasmid Plus Electroporation in Combination With Intravenous Pembrolizumab Therapy With or Without Chemotherapy in Patients With Inoperable Locally Advanced or Metastatic Triple Negative Breast Cancer (TNBC)
This is a Phase 2, Multi-Cohort, Open-Label, Multi-Center Study. Cohort 1 will be a single-arm study of intratumoral tavokinogene telseplasmid (tavo) plus electroporation (EP) in combination with pembrolizumab therapy. Cohort 2 will be a single-arm study of intratumoral tavo-EP plus pembrolizumab with nab-paclitaxel (Abraxane®) chemotherapy. Subjects with TNBC and EP accessible cutaneous / subcutaneous disease will be enrolled in this study.
Eligible subjects will be treated with intratumoral tavo-EP to the accessible lesions on Days 1, 5 and 8 every 6 weeks and with IV pembrolizumab (200 mg) on Day 1 of each 3-week cycle for up to 17 cycles of tavo-EP and 33 cycles of pembrolizumab from baseline (approximately 2 years) or until subsequent disease progression. For Cohort 2, subjects will be treated with an approved chemotherapy per standard of care, limited to nab-paclitaxel (Abraxane®). All accessible lesions, each ≥ 0.3 cm × 0.3 cm, may be treated; except where possible, 1 measurable lesion by RECIST (size ≥ 1.0 cm) should be selected and left untreated for the duration of the study.
Long-term Follow-up: All subjects will be followed after the End of Study (EOS) visit for Serious Adverse Events (SAEs) (through 90 days from the last dose of study drug) and long-term survival status for up to 1 year. EOS visit will occur 4 weeks after last study treatment administration.
18 Years and up
Accepting Healthy Volunteers?
1. Subjects with histologically confirmed diagnosis of inoperable locally advanced or metastatic TNBC.
2. For Cohort 1 only, subjects must have received at least 1 prior line of systemic chemotherapy or immunotherapy that includes an approved regimen.
3. For Cohort 2 only, subjects may only have received neoadjuvant and adjuvant treatment in the non-metastatic or operable disease setting and must not have progressed within 6 months of last dose of (neo) adjuvant therapy.
4. For both Cohorts 1 and 2, Subjects must have estrogen (ER) receptor and progesterone (PR) receptor staining <10% and be human epidermal growth factor receptor 2 (HER2) negative defined as immunohistochemistry (IHC) 0 to 1+
5. For Cohort 2 only, subjects must have PD-L1 testing per Dako 22C3 Combined Positive Score (CPS) assay performed prior to dosing. Prior testing will be acceptable if completed per required assay. Otherwise recent or newly obtained biopsy at screening will be collected for central determination of PD-L1 expression.
6. Subjects must not have disease that, in the opinion of the Investigator, is considered amenable to potentially curative treatment.
7. Age ≥ 18 years of age of day of signing informed consent.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
9. Life expectancy of at least 6 months.
10. Have measurable disease based on RECIST v1.1, and at least one anatomically distinct lesion involving skin or subcutaneous tissue accessible for electroporation of ≥ 0.3 cm and lesion must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded).
11. Demonstrate adequate organ function as defined below. All screening laboratories should be performed within 10 days of treatment initiation.
12. For women of childbearing potential, negative serum or urine pregnancy test within 72 hours prior to the first study drug administration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
13. For women of childbearing potential, must be willing to use an adequate method of contraception from 30 days prior to the first study drug administration and 120 days following last day study drug administration (either tavo or pembrolizumab). Women may be surgically sterile or at least 1-year post-last menstrual period.
14. Male subjects must be surgically sterile or must agree to use contraception during the study and at least 120 days following the last day of study drug administration.
15. Able and willing to give informed consent and to follow study instructions.
1. Subject has a known additional malignancy that is progressing or requires active treatment.
2. Clinically active central nervous system (CNS) metastases. Subjects with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study drug.
3. For Cohort 2 only, less than 6-month disease free interval from the last dose of (neo)adjuvant therapy.
4. Subject who had an allogenic tissue/solid organ transplant.
5. Subjects with electronic pacemakers or defibrillators.
6. Subject who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
7. Subjects who are known to be positive for Hepatitis B antigen (HBsAg) or Hepatitis B virus (HBV) DNA or Hepatitis C antibody or RNA. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative hepatitis C virus (HCV) RNA results greater than the lower limits of detection of the assay.
8. Subject has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
9. Subjects who have received a live-virus vaccination within 30 days of the first dose of treatment. Seasonal flu vaccines that do not contain live virus are permitted.
10. Subject has severe hypersensitivity (≥Grade 3) to pembrolizumab or other anti-PD-1 monoclonal antibody therapy and/or any of its excipients.
11. For Cohort 2 only: Subject has severe hypersensitivity (≥Grade 3) to nab-paclitaxel (Abraxane). Patient must be able to tolerate the trial approved chemotherapy.
12. Subjects who have received transfusion of blood products (including platelets or red blood cells) or colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 3 weeks prior to study Cycle 1, Day 1 (Baseline).
13. Subject has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
14. Subject has a history of interstitial lung disease.
15. Subject has an active infection requiring systemic therapy.
16. Subject has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
17. Subject has not recovered (i.e., ≤ Grade 1 or at Baseline) from adverse events (AEs) due to a previously administered agent.
18. Participation in another clinical study of an investigational anti-cancer agent or has used an investigational device within 30 days of screening.
19. Subject has known psychiatric or substance abuse disorders that would interfere with the subject's ability to cooperate with the requirements of the study.
20. Subjects who are pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the Screening visit through 120 days after the last dose of study treatment.