Inclusion Criteria:
1. Subject and/or their legally authorized representative must be capable of
understanding the investigational nature, potential risks, and benefits of the study.
The subject and/or their legally authorized representative must sign a written
informed consent;
2. Subject is ≥18 years of age upon signing the Informed Consent Form;
3. Subject has histologically or cytologically confirmed stage IV (metastatic) squamous
or non-squamous NSCLC
- Part A only:
▪ Subject has received, and then progressed or been intolerant to up to 3 lines
of prior therapy in the 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 for Part A, upon
discussion with and approval by the Sponsor.
- Subjects will be eligible for Part A irrespective of PD-L1 expression.
- Subjects will be eligible for Part A irrespective of EGFR or ALK mutation
status. However, subjects with an EGFR sensitizing mutation or ALK
translocation must have received and then progressed or been intolerant to
at least 1 prior line of approved targeted therapy to be eligible for Part
A.
- Part B only:
- Subject is undergoing treatment with pembrolizumab monotherapy for
metastatic NSCLC
- Subject's most recent tumor assessment is consistent with PD according to
RECIST v1.1
- The Investigator has determined that PD should be confirmed within 4-8
weeks, and pembrolizumab treatment will continue pending PD confirmation
- Subject is willing to undergo a confirmatory scan 4-8 weeks from the prior
scan that indicated progression on pembrolizumab
- There is no evidence of rapid disease progression or clinical deterioration
in the subject that would preclude continuation of pembrolizumab treatment
pending confirmation of PD.
- Part C only:
- Subject has received no prior systemic treatment in the metastatic setting.
Subjects previously treated with adjuvant or neoadjuvant therapy are
eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months
prior to the diagnosis of metastatic disease.
- Subject has provided a formalin-fixed tumor sample from a biopsy of a tumor
lesion either at the time of or after the diagnosis of metastatic disease
AND from a site not previously irradiated, to assess for PD-L1 status.
Biopsies obtained PRIOR to the administration of any systemic therapy to
treat the subject's tumor (such as neoadjuvant/adjuvant therapy) will not be
permitted for analysis. The tissue sample must be received by the central
laboratory vendor prior to enrollment. Fine needle aspirates, Endobronchial
Ultrasound (EBUS) or cell blocks are not acceptable. Needle or excisional
biopsies, or resected tissue is required. If the tumor specimen is not
evaluable for PD-L1 expression by the central laboratory, an additional
tumor specimen may be submitted.
- Subject's tumor has PD-L1 expression of ≥50%, as determined by
immunohistochemistry (IHC) at a central laboratory.
- Subject's tumor does not harbour an EGFR sensitizing (activating) mutation
or ALK translocation. EGFR sensitizing mutations are mutations that are
amenable to treatment with TKIs (e.g., erlotinib, gefitinib, afatanib,
osimertinib). ALK translocations are amendable to treatment with TKIs such
as crizotinib, alectinib and ceritinib. Investigators must produce the
source documentation of the EGFR mutation and ALK translocation status in
all subjects with non-squamous histology AND for subjects in whom testing is
clinically indicated. If either an EGFR sensitizing mutation or ALK
translocation is detected, additional information regarding the mutation
status of the other molecule is not required. If the clinical site is unable
to provide the source documentation, EGFR and ALK testing should be
performed per institutional standard of care.
4. Subject has measurable disease for response assessment as defined by RECIST v1.1 by
the Investigator;
5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
(see Appendix 11);
6. Subject has a life expectancy of at least 3 months;
7. Subject has recovered to Grade ≤1 by the National Cancer Institute Common Terminology
Criteria for Adverse Events, Version 4.03 (NCI-CTCAE v4.03) of all clinically
significant toxic effects of prior anti-cancer chemotherapy, immunotherapy,
radiotherapy or surgery before entering this study, except for alopecia;
8. Subject has no major existing comorbidities or medical conditions that would preclude
therapy in the opinion of the Investigator;
9. Subject has adequate organ function
10. 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
treatment period and for at least 120 days after the final dose of study
treatment;
11. A female subject of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study treatment
and throughout the study as defined in the SoA. If the urine test is positive or
cannot be confirmed as negative, a serum pregnancy test will be required.
12. A male subject is eligible if he agrees to follow the contraceptive guidance in
Appendix 5 during the treatment period and for at least 120 days after the final dose
of study treatment.
Exclusion Criteria:
1. Subject has an ongoing different primary malignancy. Exceptions include treated basal
cell carcinoma of the skin or squamous cell carcinoma of the skin;
2. Subject has an active autoimmune disease requiring systemic treatment within the past
3 months, a documented history of clinically severe autoimmune disease, or a disorder
that requires systemic corticosteroids or immunosuppressive agents. Subjects with
vitiligo, psoriasis, alopecia or resolved childhood asthma/atopy not requiring
systemic treatment would be an exception to this rule. Subjects with hypothyroidism
who are stable on hormone replacement (>10 mg daily prednisone equivalent) or
Sjögren's syndrome will not be excluded from the study;
3. Subject has a diagnosis of primary immunodeficiency, is dependent on or has received
systemic corticosteroid therapy (>10 mg daily prednisone equivalent) or any other form
of immunosuppressive therapy within 14 days prior to the first dose of study
treatment. Inhaled or topical corticosteroids, and adrenal replacement corticosteroid
doses >10 mg daily prednisone equivalent, are permitted in the absence of active
autoimmune disease;
4. Subject has neuropathy (sensory or motor) ≥Grade 3 per CTCAE v4.03;
5. Subject has had an allogeneic tissue/solid organ transplant;
6. Subject has interstitial lung disease (ILD) OR has had a history of pneumonitis that
has required oral or IV steroids;
7. Subject has untreated central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (no new or enlarging brain metastases) by imaging for at least 2 weeks
following treatment, and clinically stable with no symptoms due to CNS metastasis, and
are not using corticosteroids for at least 14 days prior to the start of study
treatment;
8. Subject has a concurrent unstable or uncontrolled medical condition (e.g., active
uncontrolled systemic infection, unstable angina, congestive heart failure,
uncontrolled diabetes) or other chronic disease, which in the opinion of the
Investigator could compromise the subject or the study;
9. Subject has a known history of human immunodeficiency virus (HIV) infection (HIV 1/2
antibodies);
10. Subject has a known active hepatitis B (e.g., HBsAg reactive) or hepatitis C infection
(e.g., HCV RNA [qualitative] is detected) or tuberculosis;
11. Subject has an 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 any study treatment);
12. Subject has known psychiatric or substance abuse disorder(s) that would interfere with
cooperation with the requirements of the study;
13. Subject has an implanted medical device that poses a high risk for bacterial
colonization and/or that cannot be easily removed (e.g., prosthetic joints, artificial
heart valves, pacemakers, orthopedic screws, metal plates, bone grafts, or other
exogenous implants). NOTE: More common devices and prosthetics that include arterial
and venous stents, dental and breast implants and venous access devices (e.g.,
Port-a-Cath or Mediport) are permitted. Sponsor must be contacted prior to consenting
any subject who has any other device or implant;
14. Subject is pregnant or breastfeeding, or plans to become pregnant or to father
children, from the Screening visit through at least 120 days after the final dose of
study treatment;
15. Subject has a contraindication (e.g., sensitivity/allergy) to trimethoprim/
sulfamethoxazole and ampicillin;
16. Subject has a contraindication to non-steroidal anti-inflammatory drugs (NSAIDs);
17. Subject has a known allergy to any component of the study formulation(s);
18. Subject has a history of listeriosis;
19. Subject has any other serious or uncontrolled physical or mental condition/disease
that, as judged by the Investigator, could place the subject at higher risk derived
from their participation in the study, could confound results of the study, or would
be likely to prevent compliance with the requirements of the study;
20. Subject has received chemotherapy and/or radiation therapy (except palliative
radiation therapy for disease-related pain) within 2 weeks of the first dose of study
treatment;
21. Subject has received monoclonal antibody or other biologic therapy within 5 half-lives
or 28 days prior to the first dose of study treatment, whichever is shorter. An
exception to this exclusion criterion will be pembrolizumab monotherapy for subjects
enrolled in Part B;
22. Subject has received prior treatment with an Lm-based immunotherapy;
23. Subject is receiving or plans to receive future treatment with PI3K or TNFα
inhibitors;
24. Subject has received a live vaccine within 30 days prior to the first dose of study
treatment;
25. Subject has not recovered to baseline from AEs, with the exception of alopecia, due to
previously administered agent(s);
26. Subject has had major surgery within 6 weeks prior to the initiation of study
treatment. NOTE:
All surgical complications must have recovered to baseline or Grade ≤1 prior to the
initiation of study therapy. Sponsor must be consulted prior to enrolling subjects on
the study who recently had a major surgery or have a new artificial implant, and/or
devices;
27. Subject is currently participating in or has participated in a study of an
investigational agent(s) within 4 weeks of the first dose of study treatment;
28. Subject is or has an immediate family member (spouse or children) who, as
investigational site or sponsor staff, is directly involved with this trial, unless
prospective IRB approval (by chair or designee) is given allowing exception to this
criterion for a specific subject;
Exclusion Criteria for Part C only
29. In Part C, subject has received systemic therapy for the treatment of their metastatic
NSCLC.
Completion of treatment with chemotherapy and/or radiation as part of
neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6
months prior to the diagnosis of metastatic disease;
30. In Part C, subject has an EGFR sensitizing mutation and/or an ALK translocation;
31. In Part C, baseline tumor specimen is not evaluable for PD-L1 expression by the
central laboratory. If an additional tumor specimen is submitted AND evaluable for
PD-L1 expression, the subject will be eligible to participate if PD-L1 expression is
assessed as ≥50% by the central laboratory;
32. In Part C, subject has received prior systemic chemotherapy, biological therapy, OR
major surgery within 6 weeks of the first dose of study treatment; received thoracic
radiation therapy of >30 Gy within 6 months of first dose of study treatment;
33. In Part C, subject has received prior therapy with an anti-PD-1, anti-PD-L1,
anti-PD-L2, anti- CD137, or anti-CTLA-4 antibody, or any other antibody or drug that
specifically targets T cell co-stimulation or immune checkpoint pathways.
