Approximately 50 ABA+ subjects with resectable, Stage III (IIIB, IIIC, or IIID) melanoma will
be included in the study and randomized in a 3:2 ratio to neoadjuvant treatment with Imprime
PGG plus pembrolizumab vs. pembrolizumab monotherapy. A baseline, reference biopsy and a
PET/CT scan will be obtained prior to commencing 3 cycles (9 weeks) of neoadjuvant treatment
with either regimen. During Week 5, subjects will provide another biopsy to assess treatment
effects on the tumor and its microenvironment. At the completion of neoadjuvant treatment and
before surgery, subjects will undergo another PET/CT scan to assess radiological and
metabolic response compared to baseline.
Approximately 50 ABA+ subjects with resectable, Stage III (IIIB, IIIC, or IIID) melanoma will
be included in the study and randomized in a 3:2 ratio to neoadjuvant treatment with Imprime
PGG plus pembrolizumab vs. pembrolizumab monotherapy. A baseline, reference biopsy and a
PET/CT scan will be obtained prior to commencing 3 cycles (9 weeks) of neoadjuvant treatment
with either regimen. During Week 5, subjects will provide another biopsy to assess treatment
effects on the tumor and its microenvironment. At the completion of neoadjuvant treatment and
before surgery, subjects will undergo another PET/CT scan to assess radiological and
metabolic response compared to baseline.
Subjects will then undergo surgical resection. A pre-surgical assessment of operability will
be done by the responsible surgeon, and the investigator will ensure that adverse events
occurring during the treatment period have resolved to the minimal acceptable level that
would not place the subject at undue risk or delay surgery for more than 1 week after the
last dose of Imprime or 3 weeks after last dose of pembrolizumab, when subjects will undergo
surgical resection.
The surgical specimen will be locally and centrally assessed by a pathologist to determine
the pathological response (pCR, pMR, pPR) induced by the neoadjuvant treatment (central read
will be blinded). Following surgery, subjects will be followed for safety for 90 days. The
total duration of systemic treatment will be 3 cycles (9 weeks). In the Investigational arm,
surgery should be performed no more than a week after the subject's last dose of Imprime PGG
and in the Control arm, surgery should be performed within 3 weeks of the subject's last dose
of pembrolizumab.
Inclusion Criteria:
1. Signed informed consent form
2. ≥18 years of age
3. Histologically confirmed diagnosis of resectable* AJCC (8th edition) Stage IIIB, IIIC
or IIID cutaneous or unknown primary melanoma (except for any in-transit or satellite
metastases) (*Resectable Stage III disease is defined as disease that is amenable to
complete tumor resection (anticipated to be an R0 resection) as judged as judged by
the responsible surgeon. Criteria to judge resectability include, but are not limited
to, lesions located in anatomically inaccessible areas, or invading vascular or neural
structures, or technical or other reasons preventing their complete removal)
4. No prior systemic treatment for melanoma (subjects who were previously resected,
relapsed and are once again resectable are eligible)
5. RECIST 1.1 measurable disease:
a.) ≥ 10mm in the longest diameter for primary (if applicable) lesions or lymph node
and/or ≥ 15mm in the shortest diameter for lymph nodes b) Sufficient nodal +/1 primary
lesions amenable to ≥ 2 excisional/ core biopsies
6. No prior radiotherapy to nodal basin
7. Subject consents to provide 2 newly obtained core or excisional biopsies from
non-nodal, non-bone lesions (within 28 days prior to C1D1 and during Wk 5 of
treatment), the use of the resected surgical specimen and additional blood samples for
translational research correlative studies
8. Have peripheral blood levels of IgG anti-β-glucan antibody (ABA) of ≥ 20 mcg/mL as
determined by an ELISA test prior to (within 90 days) start of study treatment
9. ECOG PS 0-1 (within 7 days of starting treatment)
10. Estimated life expectancy of ≥12 weeks, in the opinion of the Investigator
11. Adequate organ function, including all of the following within 15 days before Day 1:
a.) Hematological: i.) Absolute neutrophil count (ANC) ≥ 1.5×109/L (> 1,500/mm3)
(subject may not use G-CSF or GM-CSF to achieve this level) ii.) Platelets ≥ 100×109/L
(>100,000 per mm3) iii.) Hemoglobin level >9 gm/dL. Packed red blood cell transfusion
is acceptable, as long as the subject has a stable result of >9 gm/dL for at least
1week post-transfusion. Erythropoietin should not be used to achieve this level iv.)
Adequate coagulation function at screening as determined by prothrombin time (PT)
International Normalized Ratio (INR) < 1.5 times the upper limit of normal (ULN) and
partial thromboplastin time (PTT) < 1.5 times the ULN v.) Lymphocyte count >1500
cells/mL b.) Intact immune system as demonstrated by CD4 count >500 cells/mm3 and CD8
count >150 cells/mm3 c.) Renal: i.) Serum creatine or measured and calculated
creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN
and creatinine clearance ≥30 mL/min, per Cockcroft Gault formula d.) Hepatic: i.)
Serum total bilirubin ≤1.5× ULN or direct bilirubin ≤ ULN for a subject with total
bilirubin levels >1.5× ULN ii.) AST/ALT < 2.5 x ULN iii.) Albumin >3 g/dL
12. Have a negative PCR test at screening for SARS-COV-2 RNA
13. Women of childbearing potential (WOCBP) must have 2 negative serum or urine pregnancy
tests during Screening, the second within 24 hours prior to the first administration
of study drug, and must agree to use highly effective physician-approved contraception
from Screening to a minimum of 90 days following the last study drug administration
14. Willing and able to comply with all protocol-specified assessments and the study visit
schedule.
Exclusion Criteria:
1. Prior therapy for melanoma (resection of a previous melanoma lesion is acceptable)
2. Subjects with uveal or mucosal melanoma
3. Pregnant, lactating or not practicing adequate contraception (premenopausal women), or
expecting to conceive or father children within the duration of the trial, starting
from Screening to 90 days following the last dose of drug administration
4. Prior radiotherapy in the previous 2 weeks. Radiotherapy to presenting tumor is
prohibited
5. Administration of a live, attenuated vaccine within 28 days prior to Day 1 or
anticipation that such a live attenuated vaccine will be required during the study
6. History of autoimmune disease, including but not limited to inflammatory bowel
disease, systemic lupus erythematosus, and autoimmune hepatitis, requiring systemic
treatment in previous 12 months
7. Treatment with systemic corticosteroids or other systemic immunosuppressive
medications (including but not limited to prednisone [>10mg], dexamethasone,
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis
factor [TNF] agents) within 15 days prior to Day 1, or anticipated requirement for
systemic immunosuppressive medications during the trial
8. Immunodeficiency, natural or iatrogenic (steroids, immunosuppressants)
9. History of malignancy within the last 3 years. Subjects with prior history of in situ
cancer or basal or squamous cell skin cancer are eligible. Subjects with other
malignancies are eligible if they were cured by surgery alone or surgery plus
radiotherapy and have been continuously disease-free for at least 5 years
10. Known CNS metastasis of leptomeningeal disease
11. Known history of HIV, Hepatitis B, active Hepatitis C or tuberculosis
12. History of pneumonitis including interstitial lung disease
13. Has a known hypersensitivity to any component of protocol therapy, or their vehicle(s)
14. Uncontrolled concurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure (NYHA Grade 2), unstable angina
pectoris, cardiac arrhythmia, any Class 3 or 4 cardiac disease as defined by the New
York Heart Association Functional Classification or psychiatric illness
15. Has a fever >38oC within 3 days before the first dose of study treatment
16. Had previous exposure to Imprime PGG
17. 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
18. Any condition which could interfere with, or the treatment for which might interfere
with the conduct of the study or which would, in the opinion of the Investigator,
unacceptably increase the subject's risk by participating in the study
19. Subject is under legal custodianship
20. First-degree relatives of the investigator, study staff or the sponsor.
