Study of Imprime PGG and Pembrolizumab in Advanced Melanoma and Triple Negative Breast Cancer
Study of Imprime PGG and Pembrolizumab in Advanced Melanoma and Triple Negative Breast Cancer
Objective: To determine the Overall Response Rate (ORR) to Imprime PGG + pembrolizumab in
 subjects with advanced melanoma or metastatic TNBC

 Safety: To characterize the safety of Imprime PGG + pembrolizumab given in combination

 Hypothesis: Restore (for melanoma) or enhance (for TNBC) sensitivity to checkpoint inhibitors
 (CPI) by appropriate and effective stimulation of the subject's innate and adaptive immune
 systems in those subjects who have failed 1st line therapy

 The study will incorporate Simon's optimal 2-stage design with sample size fixed at 12
 subjects each in Stage 1 for advanced melanoma and for Triple Negative Breast Cancer (TNBC)
 subjects. The safety criterion of ≤ 4 (or ≤ 33%) subjects with Grade 3/4 adverse events in
 Cycle 1 within either tumor type must be met in order to proceed to Stage 2. The starting
 dose is 4 mg/kg for Imprime PGG. In the event there are a total of > 4 (or > 33%) of subjects
 with Grade 3/4 adverse events in Cycle 1, the dose of Imprime PGG will be reduced to 2 mg/kg,
 and Stage 1 will be repeated at a dose of 2 mg/kg with an additional cohort of n=12 subjects.
 For the dose that meets the safety criterion in Stage 1, at least 1 response in melanoma
 subjects and 2 responses in TNBC subjects amongst the 12 subjects within each tumor type must
 be observed in order to proceed to Stage 2.

 Stage 2 will enroll an additional 17 subjects with melanoma, and 30 subjects with TNBC. For
 the dose that meets the Stage 1 safety criterion, success will be declared if at least 4
 amongst the total of up to 29 subjects with melanoma, and 13 amongst the total of up to 42
 subjects with TNBC achieve an objective response.
Inclusion Criteria:

 1. Have signed an informed document prior to any study-specific procedures or treatment

 2. Be ≥ 18 years of age at time of consent

 3. For Melanoma Subjects: Have histologically or cytologically confirmed diagnosis of
 unresectable Stage III or metastatic (Stage IV) melanoma not amenable to local
 therapy, and irrespective of PD-L1 status

 4. For TNBC Subjects: Have histologically or cytologically confirmed diagnosis of
 metastatic (Stage IV) TNBC, and irrespective of PD-L1 status. TNBC is defined as
 negative immunohistochemistry (IHC) assays for Estrogen Receptor (ER), and
 Progesterone Receptor (PR), and HER2 negative (IHC 0 or 1+, or 2+ by IHC confirmed
 negative by FISH)

 5. Have documented objective radiographic or clinical disease progression after
 PD-1/PD-L1 +/- anti-CTLA-4 inhibitor therapy (melanoma) or after at least 1 line of
 chemotherapy for metastatic disease (TNBC)

 6. Have resolution of all previous treatment-related toxicities to Grade 1 severity or
 lower, except for stable sensory neuropathy (less than or equal to Grade 2) or
 alopecia. If subject received major surgery or radiation therapy of > 30 Gy, must have
 recovered from the toxicity and/or complications from the intervention.

 7. Have at least one radiologically measurable lesion as per RECIST v1.1 defined as a
 lesion that is at least 10 mm in longest diameter or lymph node that is at least 15 mm
 in short axis imaged by CT scan or MRI and obtained by imaging within 28 days prior to
 start of study treatment. Tumor lesions situated in a previously irradiated area are
 considered measurable if progression has been demonstrated in such lesions.

 8. Have peripheral blood levels of IgG anti-β-glucan antibody (ABA) of ≥ 20 mcg/mL as
 determined by an ELISA test within 28 days prior to start of study treatment

 9. Be willing to consider providing fresh tissue for biomarker analysis, and, based on
 the adequacy of the tissue sample quality, for assessment of biomarker status. Repeat
 samples may be required if adequate tissue is not provided. Newly obtained biopsy
 specimens are preferred to archived samples and formalin-fixed, paraffin-embedded
 block specimens are preferred to slides.

 Note: Information on 1 tumor biopsy sample is mandatory and is as follows: (1) To
 determine eligibility, historical (diagnostic) tumor biopsy official pathology report
 +/- an archival sample. Additional biopsy samples, preferably obtained from the same
 localized region, are highly desirable when feasible at the following time points: (2)
 Sample before the first dose of study treatment, (3) Sample after completion of Cycle
 2 but before the start of Cycle 3 dosing, and (4) Sample either at the time of
 response or at the End of Study Visit (if no response).

 10. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (see
 Appendix 14.3)

 11. Have life expectancy of 3 months or greater as determined by the treating physician

 12. Have adequate organ function (all screening labs should be performed within 15 days
 prior to treatment initiation):

 1. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for
 subjects with total bilirubin levels > 1.5 x ULN

 2. Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
 hepatic metastases

 3. Alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
 hepatic metastases

 13. Have adequate renal function as defined by the following criteria:

 Creatinine ≤ 1.5 x ULN and CrCl ≥ 30 ml/min per Cockcroft Gault formula:

 14. Have adequate hematologic function, defined as meeting all of the following criteria:

 1. Hemoglobin ≥ 9 g/dL (uncorrected by RBC transfusion)

 2. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L

 3. Platelet count ≥ 100 × 109/L

 15. Have adequate coagulation functioning within 15 days prior to start of study
 treatment, defined by either of the following criteria:

 1. INR < 1.5 × ULN

 2. OR for subjects receiving warfarin or low molecular weight heparin (LMWH), the
 subjects must, in the Investigator's opinion, be clinically stable with no
 evidence of active bleeding while receiving anticoagulant therapy. The INR for
 these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.

 3. Activated Partial Thromboplastin Time (aPTT) < 1.5 × ULN unless subject is
 receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
 of intended use of anticoagulants

 16. Female subjects of childbearing potential as defined in Section 5.7.2 must have a
 negative urine or serum pregnancy within 72 hours prior to receiving the first dose of
 study medication. If the urine test is positive or cannot be confirmed as negative, a
 serum pregnancy test will be required.

 17. If of childbearing potential as defined in Section 5.7.2, must be willing to use an
 adequate method of contraception (see Section 5.7.2) from the first dose of study
 medication through 120 days after the last dose of study medication

 18. Be willing and have the ability to comply with scheduled visits (including
 geographical proximity), treatment plans, laboratory tests, and other study procedures

 Exclusion Criteria:

 1. Has disease that is suitable for local therapy administered with curative intent

 2. Is 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 treatment

 3. Has a diagnosis of immunodeficiency or receiving systemic steroid therapy or any other
 form of immunosuppressive therapy within 7 days prior to the first dose of study
 treatment. The use of physiologic doses of corticosteroids may be approved after
 consultation with the Sponsor.

 4. Has known history of active tuberculosis

 5. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

 6. Has known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA
 [qualitative] is detected

 7. Has a history of clinically severe autoimmune disease, or history of organ transplant

 8. Has a history of ocular melanoma

 9. Has known hypersensitivity to baker's yeast

 10. Had previous exposure to Betafectin® or Imprime PGG

 11. Has hypersensitivity to pembrolizumab or any of its excipients

 12. Had a prior anti-cancer monoclonal antibody (except immune CPI in the case of melanoma
 subjects) within 30 days prior to start of study treatment, or failure to recover to
 CTCAE Grade 1 or better from the adverse events of prior therapies

 13. Had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
 weeks prior to Study Day 1 or who has not recovered from adverse events due to a
 previously administered agent or major surgery

 14. Has received transfusion of blood products (including platelets or red blood cells) or
 administration of colony stimulating factors (including G-CSF, GM-CSF, or recombinant
 erythropoietin) within 4 weeks prior to Study Day 1

 15. Has 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.

 16. Has 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.

 17. Has active autoimmune disease requiring systemic treatment in the past 2 years (ie,
 with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
 Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteriod replacement
 therapy for adrenal or pituitary insufficiency) is not considered a form of systemic
 treatment.

 18. Has evidence of (non-infectious) pneumonitis that required steroids or current
 pneumonitis

 19. Has a history of interstitial lung disease

 20. Has an active infection requiring systemic therapy

 21. Has a 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. Has a clinically significant cardiovascular disease such as unstable angina,
 myocardial infarction, or acute coronary syndrome within ≤180 days prior to start of
 study treatment, symptomatic or uncontrolled arrhythmia, congestive heart failure, or
 any Class 3 or 4 cardiac disease as defined by the New York Heart Association
 Functional Classification

 23. Has a known psychiatric or substance abuse disorder(s) that would interfere with
 informed consent or cooperation with the requirements of the trial

 24. Is pregnant or breastfeeding, or expecting to conceive or father children within the
 projected duration of the trial, starting with the pre-screening or screening visit
 through 120 days after the last dose of trial treatment

 25. With TNBC has received prior therapy with an anti-PD-1, anti-PD-L1, anti-CTLA-4, or
 anti-PD-L2 agent

 26. Has received a live-virus vaccination within 30 days of planned treatment start.
 Seasonal flu vaccines that do not contain live virus are permitted