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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04995094
Recruitment Status : Withdrawn (Enrollment challenges, study not feasible)
First Posted : August 6, 2021
Last Update Posted : November 5, 2021
Sponsor:
Information provided by (Responsible Party):
HiberCell, Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Pathologic Stage III Cutaneous Melanoma AJCC v8 Biological: Imprime PGG Biological: Pembrolizumab Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized
Masking: None (Open Label)
Masking Description: Open Label
Primary Purpose: Treatment
Official Title: A Phase II, Neoadjuvant, Randomized, Multicenter Study of Imprime PGG Plus Pembrolizumab in Subjects With Stage III, Resectable Melanoma
Actual Study Start Date : August 15, 2021
Estimated Primary Completion Date : February 18, 2023
Estimated Study Completion Date : May 18, 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Imprime PGG + Pembrolizumab (Investigational ARM)
Imprime PGG + Pembrolizumab (Investigational ARM)
Biological: Imprime PGG
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.
Other Name: BTH1677

Biological: Pembrolizumab
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.
Other Name: KEYTRUDA®

Active Comparator: Pembrolizumab (Control ARM)
Pembrolizumab (Control ARM)
Biological: Pembrolizumab
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.
Other Name: KEYTRUDA®




Primary Outcome Measures :
  1. Pathological Response Rate (pRR) [ Time Frame: Within 18 months of last patient enrolled ]
    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


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: Within 24 months of last patient enrolled ]
    Radiological overall response rate (ORR) (by RECIST 1.1)

  2. Incidence of Treatment-Emergent Adverse Events [ Time Frame: Within 24 months of last patient enrolled ]
    Safety of neoadjuvant treatment (incidence of treatment-emergent adverse events, change from baseline in physical findings, ECGs, and laboratory results)

  3. Metabolic Response Rate [ Time Frame: Within 24 months of last patient enrolled ]
    Metabolic Response Rate (assessed by PET per EORTC recommendations)

  4. Correlation of Metabolic Response Rate (pathological response) [ Time Frame: Within 24 months of last patient enrolled ]
    Correlation of metabolic response rate with pathological response

  5. Correlation of metabolic Response Rate (RECIST response) [ Time Frame: Within 24 months of last patient enrolled ]
    Correlation of metabolic response rate with RECIST response.

  6. Correlation of Pathological Response Rate (RECIST) [ Time Frame: Within 24 months of last patient enrolled ]
    Correlation of pathological response rate with RECIST response

  7. Incidence of Surgical Delays or Complications [ Time Frame: Within 24 months of last patient enrolled ]
    Incidence of surgical delays or complications, including post-operative infections

  8. Opinion of Operability [ Time Frame: Within 24 months of last patient enrolled ]
    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

  9. Severity of treatment-emergent adverse events [ Time Frame: Within 24 months of last patient enrolled ]
    Safety of neoadjuvant treatment (treatment-emergent adverse events, change from baseline in physical findings, ECGs, and laboratory results)


Other Outcome Measures:
  1. Circulating Tumor DNA (ctDNA) [ Time Frame: Within 24 months of last patient enrolled ]
    Measurement of circulating tumor DNA (ctDNA)

  2. Degree of Necrosis and Genetic Markers in Tumor Tissue [ Time Frame: Within 24 months of last patient enrolled ]
    Measurement of degree of necrosis and genetic markers in tumor tissue

  3. Tumor Microenvironment (TME) [ Time Frame: Within 24 months of last patient enrolled ]
    Assessment of tumor microenvironment (TME) composition in biopsies at baseline and mid-treatment (during Wk 5), and a surgical resection specimen

  4. Measurement of Immune Cell Populations (peripheral blood) [ Time Frame: Within 24 months of last patient enrolled ]
    Measurement of pre and post treatment of immune cell populations in peripheral blood

  5. Cytokine Profiles (peripheral blood) [ Time Frame: Within 24 months of last patient enrolled ]
    Assessment of cytokine profiles in peripheral blood before and during treatment

  6. Correlation of Anti-beta Glucan Antibody (ABA) [ Time Frame: Within 24 months of last patient enrolled ]
    Correlation of anti-beta glucan antibody (ABA) expression levels with pathological, clinical & translational outcomes



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04995094


Locations
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United States, California
UC San Diego Moores Cancer Center
La Jolla, California, United States, 92093-0990
Innovative Clinical Research Institute
Whittier, California, United States, 90603
United States, New York
Ichan School of Medicine at Mount Sinai
New York, New York, United States, 10029
United States, Pennsylvania
Allegheny Health Network
Pittsburgh, Pennsylvania, United States, 15212
Sponsors and Collaborators
HiberCell, Inc.
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Responsible Party: HiberCell, Inc.
ClinicalTrials.gov Identifier: NCT04995094    
Other Study ID Numbers: PGG-MEL2021
First Posted: August 6, 2021    Key Record Dates
Last Update Posted: November 5, 2021
Last Verified: October 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by HiberCell, Inc.:
Stage III
resectable
melanoma
Imprime
Imprime PGG
pembrolizumab
neoadjuvant
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents