SBRT and Oncolytic Virus Therapy Before Pembrolizumab for Metastatic TNBC and NSCLC

This is a Phase II trial to determine the efficacy and safety of stereotactic body radiation
therapy (SBRT) and in situ oncolytic virus therapy used as a window of opportunity treatment
before pembrolizumab in patients with metastatic triple negative breast cancer (TNBC) and
metastatic non-small cell lung cancer (NSCLC). In situ oncolytic virus therapy will consist
of adenovirus-mediated expression of herpes simplex virus thymidine kinase (ADV/HSV-tk) plus
valacyclovir. Male and female patients aged ≥ 18 years with histologically confirmed locally
advanced or metastatic TNBC that has relapsed on or is refractory to 1 or more lines of
standard of care therapy or histologically or cytologically confirmed metastatic NSCLC that
is immunotherapy and chemotherapy naïve or previously treated with 1 cycle of
platinum-containing chemotherapy are eligible to participate in the study. ADV/HSV-tk (5 x
1011 viral particles) in a 2-mL total volume will be injected intratumorally on Day 0 of the
study. Valacyclovir will be orally administered at a dose of 2 g three times daily for 14
days. Valacyclovir treatment will be administered 24 hours after the gene vector injection
from Day 1 to Day 15 of the study. SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be
administered over 2 weeks from Day 2 to Day 16 of the study. Pembrolizumab (200 mg) will be
administered intravenously over 30 minutes every 3 weeks starting on Day 17 of the study and
continuing until disease progression, unacceptable toxicity, or up to 24 months in patients
without disease progression. The primary endpoint will be the objective response rate of
ADV/HSV-tk + valacyclovir therapy in combination with SBRT used as a window of opportunity
treatment before pembrolizumab in patients with metastatic TNBC and metastatic NSCLC. RECIST
1.1 will be used to assess treatment response. Secondary endpoints will include a) clinical
benefit rate; b) duration of response; c) overall survival and progression-free survival
rates; d) toxicity (toxicity will be defined as any treatment-related death or any ≥ grade 3
toxicity excluding alopecia and constitutional symptoms as assessed by the NCI CTCAE v4.03);
and e) antitumor activity of ADV/HSV-tk plus valacyclovir therapy in combination with SBRT
used as a window of opportunity treatment before pembrolizumab.

Inclusion Criteria:

1. Willing and able to provide written informed consent/assent for the trial.

2. Male or female aged ≥18 years on the day of informed consent signing.

3. Histologically confirmed locally advanced or metastatic TNBC that has relapsed on or
is refractory to standard of care therapy OR histologically or cytologically confirmed
metastatic NSCLC that is immunotherapy and chemotherapy naïve or previously treated
with 1 cycle of platinum-containing chemotherapy. Epidermal growth factor receptor
(EGFR)/anaplastic lymphoma kinase (ALK) mutation-negative NSCLC patients and NSCLC
patients with EGFR or ALK genomic tumor aberrations that have failed FDA-approved
targeted therapy for these aberrations will be eligible for enrollment in the study.

4. Measurable disease based on RECIST 1.1, a target lesion of suitable diameter (at least
1 cm) for SBRT, and a non-target lesion (visceral metastatic lesion) at least 1 cm in
diameter for abscopal effect evaluation.

5. Willing to provide biopsy tissues as required by the study.

6. Eastern Cooperative Oncology Group performance status of 0 or 1.

7. Adequate organ function as defined by the following laboratory values:

- Absolute neutrophil count ≥1,500/µL (without granulocyte colony stimulating
factor support within 14 days of assessment)

- Platelets ≥100,000/µL

- Hemoglobin ≥8 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin
dependency (within 7 days of assessment)

- White blood cell count >2,500/µL and <15,000/µL

- Lymphocyte count ≥500/µL

- Serum creatinine <2 X upper limit of normal (ULN)

- Serum total bilirubin ≤1.0 X ULN (Subjects with known Gilbert's disease who have
serum bilirubin level ≤3 X ULN may be enrolled)

- Asparate transaminase and alanine transaminase ≤2.5 X ULN with normal alkaline
phosphatase (≤5 X ULN for subjects with liver metastases) OR ≤1.5 X ULN in
conjunction with alkaline phosphatase >2.5 X ULN

- Albumin >2.5 mg/dL

- International normalized ratio or prothrombin time (PT) ≤1.5 X ULN unless subject
is receiving anticoagulant therapy as long as PT or activated partial
thromboplastin time (aPTT) is within therapeutic range of intended use of
anticoagulants

- aPTT ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT
or aPTT is within therapeutic range of intended use of anticoagulants

8. Life expectancy ≥ 6 months.

9. ≥ 4 weeks since any major surgery, completion of radiation therapy, or completion of
all prior systemic anticancer therapy (adequately recovered from the acute toxicities
of any prior therapy).

10. Female subjects of childbearing potential should have a negative serum pregnancy
(beta-human chorionic gonadotropin) within 7 days prior to receiving the first dose of
the trial treatment and should not be lactating.

11. Female subjects of childbearing potential must be willing to use an adequate method of
contraception for the course of the study through 120 days after the last dose of
study therapy.

12. Male subjects of childbearing potential must agree to use an adequate method of
contraception for the course of the study through 120 days after the last dose of
study therapy.

Exclusion Criteria:

1. Unwilling or unable to comply with the study protocol.

2. Subjects for who bone metastases are the only available non-target lesions for
abscopal effect evaluation.

3. Subjects with tumors for which SBRT is not considered appropriate standard therapy.
This includes subjects with target lesions less than 1 cm in diameter and those with
large central lung lesions.

4. Currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigational device
within 4 weeks of the first dose of trial treatment.

5. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.

6. Known history of active tuberculosis (Bacillus Tuberculosis).

7. Known or suspected hypersensitivity to pembrolizumab or any of its excipients or any
component of the proposed regimen (gene vector/valacyclovir).

8. Known gallbladder or bile duct disease (i.e., infection or cholecystitis) or acute or
chronic pancreatitis.

9. Eastern Cooperative Oncology Group performance status of ≥2 or oxygen dependence
(e.g., advanced chronic obstructive pulmonary disease).

10. Inability to swallow food or any condition of the upper gastrointestinal tract that
precludes administration of oral medications (valacyclovir).

11. Congestive heart failure: New York Association class III or IV heart failure or
unstable angina.

12. Sustained or clinically significant cardiac arrhythmias including sustained
ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia,
advanced heart block (Mobitz II or higher atrioventricular nodal block), prolonged
corrected QT interval (longer than 470 milliseconds), or history of acute myocardial
infarction.

13. Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by
diabetes or Parkinson's disease), human immunodeficiency virus (HIV), cirrhosis,
uncontrolled hypothyroidism, or cardiac failure.

14. History of syncope or family history of idiopathic sudden death.

15. Targeted small molecule therapy or monoclonal antibody or radiation therapy within 3
weeks prior to study Day 0 or has not recovered (i.e., ≤ Grade 1 or at baseline) from
adverse events due to a previously administered agent.

- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may
qualify for the study.

16. Known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

17. Known active central nervous system metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least 4 weeks prior to the
first dose of trial treatment and any neurologic symptoms have returned to baseline),
have no evidence of new or enlarging brain metastases, and are not using steroids for
at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis, which is excluded regardless of clinical stability.

18. Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

19. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.

20. Active infection requiring systemic therapy.

21. History or current evidence of any condition, therapy, or laboratory abnormality that
might confound the results of the trial, interfere with the subject's participation
for the full duration of the trial, or is not in the best interest of the subject to
participate, in the opinion of the treating investigator.

22. Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial.

23. Pregnant or breastfeeding, expecting to conceive or father children within the
projected duration of the trial, starting with the prescreening or screening visit
through 120 days after the last dose of trial treatment, or is unwilling to practice
an effective method of birth control. Women of childbearing potential must have a
negative serum pregnancy test within 7 days prior to administration of trial
treatment.

24. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

25. Prior treatment with immunomodulatory therapy, immunotherapy, and/or gene vector
therapy.

26. Received prior systemic cytotoxic chemotherapy for metastatic disease (NSCLC cohort).

27. Known history of HIV (HIV 1/2 antibodies).

28. History of liver disease such as cirrhosis or known active hepatitis B (e.g.,
hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus RNA
[qualitative] is detected).

29. History of or current alcohol misuse/abuse within the past 12 months.

30. Major surgery within 4 weeks prior to study enrollment.

31. Received a live vaccine within 30 days of planned start of trial therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines and are not allowed.