Study of Neoadjuvant Imprime PGG and Pembrolizumab for Stage III, Resectable Melanoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II, Neoadjuvant, Randomized, Multicenter Study of Imprime PGG Plus Pembrolizumab in Subjects With Stage III, Resectable Melanoma

Conditions
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Pathologic Stage III Cutaneous Melanoma AJCC v8

Intervention / Treatment
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* Biological: Imprime PGG
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form ≥18 years of age 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) No prior systemic treatment for melanoma (subjects who were previously resected, relapsed and are once again resectable are eligible) 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 No prior radiotherapy to nodal basin 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 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 ECOG PS 0-1 (within 7 days of starting treatment) Estimated life expectancy of ≥12 weeks, in the opinion of the Investigator 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 Have a negative PCR test at screening for SARS-COV-2 RNA 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 Willing and able to comply with all protocol-specified assessments and the study visit schedule. Exclusion Criteria: Prior therapy for melanoma (resection of a previous melanoma lesion is acceptable) Subjects with uveal or mucosal melanoma 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 Prior radiotherapy in the previous 2 weeks. Radiotherapy to presenting tumor is prohibited 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 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 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 Immunodeficiency, natural or iatrogenic (steroids, immunosuppressants) 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 Known CNS metastasis of leptomeningeal disease Known history of HIV, Hepatitis B, active Hepatitis C or tuberculosis History of pneumonitis including interstitial lung disease Has a known hypersensitivity to any component of protocol therapy, or their vehicle(s) 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 Has a fever >38oC within 3 days before the first dose of study treatment Had previous exposure to Imprime PGG 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 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 Subject is under legal custodianship First-degree relatives of the investigator, study staff or the sponsor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imprime PGG + Pembrolizumab (Investigational ARM)<br>Imprime PGG + Pembrolizumab (Investigational ARM) | Biological: Imprime PGG<br>* Imprime PGG is a soluble, β-1,3/1,6 glucan isolated from the cell wall of a proprietary Saccharomyces cerevisiae yeast strain. Imprime PGG acts as a Pathogen-Associated Molecular Pattern (PAMP). Imprime will be administered at a dose of 4 mg/kg IV over a 2-hour infusion time on Days 1, 8 and 15 of each 3-week treatment cycle.<br>* Other names: BTH1677;Biological: Pembrolizumab<br>* Pembrolizumab is a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein. Pembrolizumab will be administered at 200 mg IV Q3W for 9 weeks.<br>* Other names: KEYTRUDA®;|
| Active Comparator: Pembrolizumab (Control ARM)<br>Pembrolizumab (Control ARM) | Biological: Pembrolizumab<br>* Pembrolizumab is a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein. Pembrolizumab will be administered at 200 mg IV Q3W for 9 weeks.<br>* Other names: KEYTRUDA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Response Rate (pRR) | To determine the pathological response rate (pRR) in the surgically resected specimen post completion of neoadjuvant therapy with Imprime PGG plus pembrolizumab vs pembrolizumab monotherapy | Within 18 months of last patient enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Radiological overall response rate (ORR) (by RECIST 1.1) | Within 24 months of last patient enrolled | 
| Incidence of Treatment-Emergent Adverse Events | Safety of neoadjuvant treatment (incidence of treatment-emergent adverse events, change from baseline in physical findings, ECGs, and laboratory results) | Within 24 months of last patient enrolled | 
| Metabolic Response Rate | Metabolic Response Rate (assessed by PET per EORTC recommendations) | Within 24 months of last patient enrolled | 
| Correlation of Metabolic Response Rate (pathological response) | Correlation of metabolic response rate with pathological response | Within 24 months of last patient enrolled | 
| Correlation of metabolic Response Rate (RECIST response) | Correlation of metabolic response rate with RECIST response. | Within 24 months of last patient enrolled | 
| Correlation of Pathological Response Rate (RECIST) | Correlation of pathological response rate with RECIST response | Within 24 months of last patient enrolled | 
| Incidence of Surgical Delays or Complications | Incidence of surgical delays or complications, including post-operative infections | Within 24 months of last patient enrolled | 
| Opinion of Operability | Comparison pre and post treatment portion of participants with disease amendable to complete tumor resection as judged by the responsible surgeon to compare surgeon's opinion of operability | Within 24 months of last patient enrolled | 
| Severity of treatment-emergent adverse events | Safety of neoadjuvant treatment (treatment-emergent adverse events, change from baseline in physical findings, ECGs, and laboratory results) | Within 24 months of last patient enrolled | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage III, resectable, melanoma, Imprime, Imprime PGG, pembrolizumab, neoadjuvant