Mutation-derived tumor antigens, which are often unique to each patient's tumor, represent a
new source of targets for cancer immunotherapy. These mutations, which arise during
tumorigenesis, are expressed only by the tumor and, as such, may be recognized as newly
formed antigens, or neoantigens, by the patient's T cells. The lack of expression of
patient-specific tumor mutations in nonmalignant cells suggests that vaccines targeting these
tumor mutations have a low risk of autoimmunity and may represent a safer therapeutic
approach than many of those currently available. The development of a Listeria monocytogenes
(Lm)-based vaccine that expresses these patient-specific tumor antigens and that activates
tumor-killing T cells has the potential to be a highly effective form of immunotherapy. In
addition, the Lm platform, because it mediates tumor control through multiple mechanisms, may
exhibit more robust anti-tumor activity than other vaccine platforms. Thus, the targeting of
patient-specific mutation-derived tumor antigens and the concurrent stimulation of host
immunity provides a rational approach for boosting anti-tumor immunity, as monotherapy and in
combination with anti-PD-1 inhibitors.
1. ≥18 years of age on the day of signing informed consent.
2. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Screening tumor biopsy must be adequate for the identification of NSMs by whole exome
sequencing and for the development of ADXS-NEO. Biopsies may be repeated for subjects
whose Screening biopsies are found to be inadequate for the development of ADXS-NEO.
Biopsy should be excisional, incisional or core needle. Fine needle aspiration is
4. Subject population for Part A (ADXS-NEO monotherapy) is as follows:
1. Histological or cytological diagnosis of metastatic CRC excluding known MSI-high
sub-types, metastatic SCCHN or metastatic NSCLC that have progressed or have
become intolerant to standard therapy, and whose disease may allow management
with other available therapies (or a treatment break, if appropriate) for up to
approximately 12 weeks following Screening tumor biopsy. More than one form of
anti-tumor therapy is allowed during this interval.
2. For metastatic CRC, up to 4 lines of approved therapy in the advanced or
metastatic setting are allowed, including approved antibody and targeted agent
therapy. Subjects may be eligible if they have received additional lines of
therapy upon discussion with and approval by the Sponsor. Subjects are excluded
if they are known to have MSI-high tumors. If the status of microsatellite
stability is not known, subjects are eligible. The determination of
microsatellite stability for CRC may be made by local testing on any available
tissue prior to study entry.
3. For metastatic SCCHN, up to 2 lines of approved therapy in the advanced or
metastatic setting are allowed, including approved antibody therapy and
immunotherapy if eligible. Subjects may be eligible if they have received
additional lines of therapy upon discussion with and approval by the Sponsor.
4. For metastatic NSCLC, up to 3 lines of approved therapy in the advanced or
metastatic setting are allowed, including approved antibodies, targeted agents
and immunotherapy if eligible. Tumors harboring squamous and/or non-squamous
histologies are eligible. Tumors harboring squamous and/or non-squamous
histologies with neuroendocrine or small cell components may be eligible upon
discussion with and approval by the Sponsor.
5. Prior exposure to immunotherapy including, but not limited to, anti-PD1 or
anti-PDL1 antibodies is allowed but not required. Subjects who received prior
treatment with such agents must meet the following criteria: (a) Full resolution
of prior checkpoint inhibitor-related adverse events and no treatment for these
adverse events for at least 3 weeks prior to the first infusion of ADXS-NEO; and
(b) no history of severe immune related adverse events (irAE) from prior exposure
to checkpoint inhibitors. Severe irAEs are defined as any CTCAE Grade 4 toxicity
requiring treatment with corticosteroids or Grade 3 toxicity requiring
corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose)
for greater than 12 weeks.
5. Subject population for Part B and Part C (ADXS-NEO + pembrolizumab) is as follows:
1. Histological or cytological diagnosis of NSCLC, SCCHN, urothelial carcinoma, or
2. Subject has received, and then progressed or been intolerant to up to 3 lines of
prior therapy in the advanced or metastatic setting, including approved
chemotherapy, targeted therapy, immunotherapy and antibody therapy, if eligible.
Subjects who have received >3 lines of prior therapy may be eligible upon
discussion with and approval by the Sponsor.
3. For NSCLC: subjects with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as
determined by an FDA-approved test are eligible, with disease progression on or
after platinum-containing chemotherapy. Subjects with EGFR or ALK genomic tumor
aberrations should have disease progression on FDA-approved therapy for these
aberrations prior to enrolment.
4. For SCCHN: subjects with recurrent or metastatic SCCHN with disease progression
on or after platinum-containing chemotherapy are eligible.
5. For urothelial carcinoma:
i. Subjects with locally advanced or metastatic urothelial carcinoma who are not
eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1
[Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or subjects
who are not eligible for any platinum-containing chemotherapy regardless of PD-L1
status, are eligible.
ii. Subjects with locally advanced or metastatic urothelial carcinoma who have disease
progression during or following platinum-containing chemotherapy or within 12 months
of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy, are
f. For melanoma: subjects with unresectable or metastatic melanoma are eligible.
6. Has evaluable or measurable disease for response assessment per RECIST v1.1.
7. Has adequate organ function as defined in Appendix 2 (Eligibility criteria).
8. Has no major existing comorbidities or medical conditions that will preclude therapy
in the view of the Investigator.
9. Baseline blood oxygen saturation on room air of > 95%
10. Resolution to Grade ≤1 by the National Cancer Institute Common Terminology Criteria
for Adverse Events, Version 4.03 (NCI-CTCAE v 4.03) of all clinically significant
toxic effects of prior anti-tumor therapy within 3 weeks of first dose of study
treatment except for alopecia.
11. A female subject is eligible to participate if she is not pregnant (see Appendix 5),
not breastfeeding, and at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 OR
2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the
study treatment period and for at least 120 days after the last dose of study
12. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving any dose of ADXS-NEO. If the urine
test is positive or cannot be confirmed as negative, a serum pregnancy test will be
13. A male subject is eligible to participate if he agrees to follow the contraceptive
guidance during the study treatment period and for at least 120 days after the last
dose of study treatment.
14. Provide written informed consent for the trial including mandatory biopsy of
accessible lesion(s) during Screening (Parts A, B and C), and mandatory on-treatment
biopsy (Parts A and B; if there is no complete resolution of lesions and if the safety
risk for biopsy remains acceptable).
1. Has a newly diagnosed tumor and a curative treatment option or approved therapy is
2. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided that 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 first dose of ADXS-NEO (Part A) or pembrolizumab
(Part B and Part C). If a subject does not meet these criteria, the subject may be
eligible upon discussion and agreement between the Sponsor and Investigator based upon
the subject's specific case.
3. Any active autoimmune disease or a documented history of autoimmune disease, or
history of a syndrome that required systemic steroids or immunosuppressive
medications, except for subjects with ≤ Grade 2 vitiligo or resolved childhood
asthma/atopy or uncomplicated dermatitis.
4. History of recently (within previous 12 months) active diverticulitis, symptomatic
peptic ulcer disease, colitis, inflammatory bowel disease or any gastrointestinal
diseases that, in the opinion of the Investigator and Sponsor's medical monitor would
pose a risk to the subject safety.
5. History of other active malignancy for < 2 years prior to enrollment. Basal cell
carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cancer that has
undergone potentially curative therapy or is felt by the Investigator to be at low
risk for recurrence is allowed.
6. History or evidence of cardiovascular risk including any of the following:
1. History or evidence of clinically significant arrhythmias (ventricular
fibrillation, ventricular tachycardia, supraventricular tachycardia, atrial
tachycardia/flutter, atrial fibrillation with rapid ventricular response, second
or third degree atrioventricular block, and sick sinus syndrome).
Exception: Subjects with controlled atrial fibrillation for >30 days prior to
enrollment are eligible. Controlled atrial fibrillation is defined as atrial
fibrillation with no ventricular response which requires no change in
medication/dosage or addition of new medication or hospital admission within 30
days prior to enrollment.
2. History of acute coronary syndromes (e.g., myocardial infarction and unstable
angina) and/or coronary angioplasty within 6 months prior to enrollment.
3. History or evidence of ≥ Class II congestive heart failure as defined by New York
Heart Association (NYHA).
4. Chronic hypertension (defined as a systolic blood pressure >140 mm Hg and/or
diastolic blood pressure >90 mm Hg which cannot be controlled by
5. Subjects with intra-cardiac defibrillators.
6. Abnormal cardiac valve morphology (≥Grade 2). Subjects with grade 1 abnormalities
can be entered on study. Subjects with moderate valvular thickening should not be
entered on study. History of arterial thrombosis (e.g., stroke or transient
ischemic attack) in the past 3 months.
7. Psychiatric or substance abuse disorders that would interfere with cooperation with
the requirements of the trial.
8. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the Screening visit(s) through 120 days
after the last dose of study treatment.
9. Active infection requiring systemic therapy or is dependent on or currently receiving
antibiotics that cannot be discontinued before dosing. (NOTE: Subjects who discontinue
an antibiotic prior to dosing must wait at least 5 half-lives after the last dose of
antibiotic before receiving ADXS-NEO (Part A) or pembrolizumab (Part B and Part C).
10. Treatment with immune modulators including, but not limited to, chronic
immunosuppressive dose of corticosteroid (>10 mg/day of prednisone or equivalent),
cyclosporine, or tacrolimus within 4 weeks prior to enrollment. If the subject was
receiving corticosteroids, taper or discontinuation must be completed at least 1 week
prior to the first dose of ADXS-NEO (Part A) or pembrolizumab (Part B and Part C).
Occasional topical corticosteroids and/or inhaled corticosteroids are allowed for a
dose equivalency of ≤10 mg prednisone taken orally per week.
11. Known allergy to any component of the study treatment formulation(s).
12. Known history of human immunodeficiency virus (HIV).
13. Known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA
[qualitative] is detected).
14. Implanted medical device(s) that pose a high risk for colonization and/or cannot be
easily removed (e.g., prosthetic joints, artificial heart valves, pacemakers,
defibrillators, orthopedic screw[s], metal plate[s], bone graft[s], or other
implant[s]). NOTE: More common devices and prosthetics that include arterial and
venous stents, dental and breast implants, urinary catheters, and venous access
devices (e.g., Port-a-Cath or Mediport) are permitted. The Sponsor must be contacted
prior to consenting any participant who has any other device and/or implant.
15. Contraindication (i.e., documented sensitivity/allergy) to
trimethoprim/sulfamethoxazole and ampicillin.
16. Contraindication to non-steroidal anti-inflammatory drugs (NSAIDs).
17. In the opinion of the investigator, participant has rapidly progressing disease, OR
has life expectancy <6 months, OR would be unable to receive at least one dose of
18. Monoclonal antibody or biologic therapy within 5 half-lives or 28 days, whichever is
shorter, prior to first dose of ADXS-NEO (Part A) or pembrolizumab (Part B and Part
C). Subjects undergoing therapy with pembrolizumab at the time of Screening (Part B)
may continue pembrolizumab without the above-mentioned washout period if stable.
19. Received anticancer chemotherapy, surgical treatment, and/or radiation therapy (except
palliative radiation therapy for disease-related pain in consultation with the
Sponsor's medical monitor) within 3 weeks of first dose of ADXS-NEO (Part A) or
pembrolizumab (Part B and Part C).
20. Because of a possible interaction between attenuated Lm and PI3K inhibitor (may be
directly involved in regulation of TNFα production and enhance Lm virulence)
(Hochdorfer 2011; Smith, 2007; Sonje 2010), subjects receiving a PI3K or TNFα
inhibitor within 3 weeks of first dose of study treatment, or are expected to receive
such agents at any time during the treatment period, are excluded.
21. Received a live vaccine within 30 days prior to the first dose of ADXS-NEO (Part A) or
pembrolizumab (Part B and Part C).
22. Major surgery, including surgery for a new artificial implant and/or medical device,
which is permitted by the protocol, within 6 weeks prior to initiation of ADXS-NEO
(Part A) or pembrolizumab (Part B and Part C). NOTE: All toxicities and/or
complications must have recovered to baseline or Grade 1 prior to the initiation of
study treatment. Consult with the Sponsor prior to enrolling participants who recently
had major surgery or who have a new artificial implant, and/or devices.
Prior/Concurrent Clinical Study Experience
23. Currently participating in or has participated in a study of an investigational agent
or is using an investigational device within 3 weeks of enrollment.