Pembrolizumab + Imprime PGG for Metastatic Non-small Cell Lung Cancer After Progression on First-Line Therapy: Big Ten Cancer Research Consortium BTCRC-LUN15-017

OUTLINE: This is a multi-center study.

The phase Ib dose escalation will evaluate the combination of pembrolizumab and Imprime PGG
for subjects with metastatic non-small cell lung cancer (NSCLC) after progression on
first-line platinum-based chemotherapy. The phase II trial will test whether addition of
Imprime PGG to pembrolizumab will increase median progression-free survival (PFS) in second
line therapy setting in NSCLC.

PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:

Cohort 1 will consist of 3-6 patients who will receive

- Imprime PGG 2 mg/kg IV on Days 1, 8, 15 for Cycles 1-4

- Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16

- Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)

Cohort 2 will consist of 3-6 patients who will receive

- Imprime PGG 4 mg/kg IV on Days 1, 8, 15 for Cycles 1-4

- Imprime PGG 2 mb/kg IV on Day 1 for Cycles 5-16

- Pembrolizumab 200 mg IV on Day 1 (cycle = 21 days)

If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of
therapy, an additional three subjects will be enrolled at dose level 2. If all subjects in
dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be
enrolled into dose level 2 to ensure only 0-1 of 6 subjects have a DLT. There will be no
further escalation beyond dose level 2.

PHASE II INVESTIGATIONAL TREATMENT:

Pembrolizumab will be given on Day 1 of each 21 day cycle after Imprime PGG, and the RP2D
dose of Imprime PGG will be given on Days 1, 8 and 15 of each 21 day cycle. Treatment will
continue up to 16 cycles, or until disease progression, unacceptable toxicity, subject
refusal, or subject death either from progression of disease, the therapy itself, or from
other causes.

Life expectancy: of 6 months or greater

The following baseline labs must be completed within 28 days prior to registration for
protocol therapy:

Hepatic:

- total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for
subjects with total bilirubin levels > 1.5 x ULN (except subject with Gilbert's
Syndrome, who can have total bilirubin < 3.0 mg/dl)

- aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
hepatic metastases

- alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic
metastases

Renal:

- Serum creatinine ≤ 3 mg/dL OR

- if serum creatinine > 3mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 mL/min

Hematopoietic:

- hemoglobin ≥ 9 g/dL, subjects requiring transfusion will not be eligible to start study

- and absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L

- and platelet count ≥ 100 × 10^9/L

Coagulation:

- INR < 1.5 × ULN OR

- for subjects receiving anticoagulant, the subjects must, in the investigator's opinion,
be clinically stable with no evidence of active bleeding while receiving anticoagulant
therapy. The INR for subjects on warfarin should be in the therapeutic range. Low
molecular weight heparin (LMWH) is allowed.

Inclusion Criteria:

- Male or female ≥ 18 years of age at time of consent.

- Subjects with histologically or cytologically confirmed non-small cell lung cancer
(NCSLC).

- Subjects with stage IV non-small cell lung cancer as defined by American Joint
Committee on Cancer (AJCC).

- Phase Ib: Subjects who progressed after first-line platinum-based chemotherapy and who
are candidates for second-line therapy.

- Phase II: Subjects who have progressed on first-line systemic therapy (either
platinum-based chemotherapy with or without immune checkpoint inhibitor or immune
checkpoint inhibitor as first line therapy) who are candidates for second-line
systemic therapy.

- Phase II: Subjects with an EGFR or ALK mutation who are no longer candidates for TKI
therapy and have progressed on standard systemic therapy (either platinum-based
chemotherapy with or without immune checkpoint inhibitor or immune checkpoint
inhibitor as first line therapy).

- Phase II only: Measurable disease according to RECIST v1.1 (Section 8) obtained by
imaging within 28 days prior to study registration. Phase Ib: subjects may enroll with
or without measurable disease.

- Phase II only: Subjects must have presence of peripheral blood levels of IgG
anti-β-glucan antibody (ABA) of ≥ 20 μg/mL as determined by an ELISA test within 90
days prior to study registration.

- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
within 28 days prior to study registration.

- Life expectancy of 6 months or greater as determined by the treating physician.

- Adequate hepatic function within 28 days prior to study registration defined as
meeting all of the following criteria:

- total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for
subjects with total bilirubin levels > 1.5 x ULN (except subject with Gilbert's
Syndrome, who can have total bilirubin < 3.0 mg/dl)

- aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
hepatic metastases

- alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
hepatic metastases

- Adequate renal function within 28 days prior to study registration defined by either
of the following criteria:

- Serum creatinine ≤ 3 mg/dL

- if serum creatinine > 3mg/dL, estimated glomerular filtration rate (GFR) ≥ 20
mL/min

- Adequate hematologic function within 28 days prior to study registration defined as
meeting all of the following criteria:

- hemoglobin ≥ 9 g/dL; subjects requiring transfusion will be eligible to start
study

- and absolute neutrophil count (ANC) ≥ 1.5 × 109/L

- and platelet count ≥ 100 × 109/L

- Adequate coagulation functioning within 28 days prior to study registration defined by
either of the following criteria:

- INR < 1.5 × ULN

- for subjects receiving anticoagulant, the subjects must, in the investigator's
opinion, be clinically stable with no evidence of active bleeding while receiving
anticoagulant therapy. The INR for subjects on warfarin should be in the
therapeutic range. Low molecular weight heparin (LMWH) is allowed.

- Provided written informed consent and HIPAA authorization for release of personal
health information, approved by an Institutional Review Board (IRB). NOTE: HIPAA
authorization may be included in the informed consent or obtained separately.

- Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A
negative serum or urine pregnancy test is required within 72 hours of study
registration. If the urine test cannot be confirmed as negative, a serum pregnancy
test will be required.

- Women of childbearing potential (WOCP) must be willing to use two effective methods of
birth control such as an oral, implantable, injectable, or transdermal hormonal
contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms,
sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total
abstinence for the course of the study until 120 days after the last dose of study
drug. NOTE: Women are considered to be of childbearing potential unless they are
postmenopausal (≥45 years of age and has not had menses for greater than 12
consecutive months), surgically sterile (bilateral tubal ligation, bilateral
oophorectomy, or hysterectomy) or not heterosexually active for the duration of the
study and at least 120 days after the last dose of study drug.

- Men who are not surgically sterile (vasectomy) must agree to use an acceptable method
of contraception. Male subjects with female sexual partners who are pregnant, possibly
pregnant, or who could become pregnant during the study must agree to use condoms from
the first dose of study drug through at least 120 days after the last dose of study
drug. Total abstinence for the same study period is an acceptable alternative.

- Willingness and ability to comply with scheduled visits (including geographical
distance), treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

- Surgery within 4 weeks prior to study registration except for minor procedures. NOTE:
Hepatic biliary stent placement is allowed. NOTE: Subject must have adequately
recovered from the toxicity and/or complications of major surgery prior to study
registration, as determined by the treating physician.

- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Subjects with neurological symptoms must undergo a head CT scan or brain MRI to
exclude brain metastasis. NOTE: Subjects with previously treated brain metastases may
participate provided

- they are stable (without evidence of progression by imaging for at least four 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 study registration. This exception
does not include carcinomatous meningitis, which is excluded regardless of clinical
stability.

- Previously received a solid organ transplant or allogeneic progenitor/stem cell
transplant.

- Received a live vaccine within 30 days prior to the first dose of trial treatment.
Examples of live vaccines include, but are not limited to: measles, mumps, rubella,
chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza
vaccines for injection are generally killed virus vaccines and are allowed; however,
intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are
not allowed.

- History of blood clots, pulmonary embolism, or deep vein thrombosis unless on adequate
anticoagulant therapy as determined by the treating investigator (subject must be on
stable dose for 2 weeks).

- Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies].

- Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 7 days prior to study registration.

- Has 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) or a documented history of clinically severe autoimmune disease, or a syndrome
that requires systemic steroids or immunosuppressive agents. NOTE: 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.

- Received prior chemotherapy, an immune checkpoint inhibitor, or radiation therapy
within 2 weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1
or at baseline) from adverse events from previously administered agents. NOTE:
Subjects with alopecia, grade ≤ 2 sensory neuropathy or other grade ≤ 2 AEs not
constituting a safety risk based on investigator judgement are an exception to this
criterion and can still be considered for the study.

- Any clinically significant infection defined as any acute viral, bacterial, or fungal
infection that requires specific treatment. NOTE: Anti-infective treatment must be
completed ≥ 7 days prior to study registration.

- Has history of (non-infectious) pneumonitis that required steroids, evidence of
interstitial lung disease or active, non-infectious pneumonitis.

- Known history of active tuberculosis.

- Any other severe, uncontrolled medical condition, including uncontrolled diabetes
mellitus (defined as a Hemoglobin A1C ≥ 9% in subjects with a prior history of
diabetes, 28 days prior to study registration) or unstable congestive heart failure
(Stage III-IV of the New York Heart Association Functional Classification)

- Previous known allergy or intolerance to pembrolizumab or any of its excipients

- Previous exposure or known allergy to Imprime PGG or any of its excipients

- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration, interfere with protocol compliance, or may
interfere with the interpretation of study results and, in the judgment of the
investigator, would make the subject inappropriate for enrollment in this study.

- Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study
registration.

- Any mental or medical condition that prevents the subject from giving informed consent
or participating in the trial.

- No prior malignancy is allowed except for adequately treated basal cell or squamous
cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate cancers, or
other cancer for which the subject has been disease-free for at least 5 years.

- Treatment with any therapeutic investigational agent within 28 days prior to study
registration.